Muscarinic antagonists

ABSTRACT

Di-N-substituted piperazine or 1,4 di-substituted piperadine compounds in accordance with formula I (including all isomers, salts, esters, and solvates)  
                 
 
     wherein R, R 1 , R 2 , R 3 , R 4 , R 21 , R 27 , R 28 , X, Y, and Z are as defined herein are muscarinic antagonists useful for treating cognitive disorders such as Alzheimer&#39;s disease. Pharmaceutical compositions and methods of preparation are also disclosed. Also disclosed are synergistic combinations of compounds of the above formula or other compounds capable of enhancing acetylcholine release with acetylcholinesterase inhibitors.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to di-N-substituted piperazines and1,4-di-substituted piperidines useful in the treatment of cognitivedisorders, pharmaceutical compositions containing the compounds, methodsof treatment using the compounds, and to the use of said compounds incombination with acetylcholinesterase inhibitors.

[0002] Alzheimer's disease and other cognitive disorders have receivedmuch attention lately, yet treatments for these diseases have not beenvery successful. According to Melchiorre et al. (J. Med. Chem. (1993),36, 3734-3737), compounds that selectively antagonize M2 muscarinicreceptors, especially in relation to M1 muscarinic receptors, shouldpossess activity against cognitive disorders. Baumgold et al. (Eur. J.of Pharmacol., 251, (1994) 315-317) disclose 3-α-chloroimperialine as ahighly selective m2 muscarinic antagonist.

[0003] The present invention is predicated on the discovery of a classof di-N-substituted piperazines and 1,4-di-substituted piperidines, someof which have m2 selectivity even higher than that of3-α-chloroimperialine. Logemann et al (Brit. J. Pharmacol. (1961), 17,286-296) describe certain di-N-substituted piperazines, but these aredifferent from the inventive compounds of the present invention.Furthermore, the compounds of Logemann et al. are not disclosed to haveactivity against cognitive disorders.

SUMMARY OF THE INVENTION

[0004] The present invention relates to compounds according to thestructural formula I,

[0005] including all isomers and pharmaceutically acceptable salts,esters, and solvates thereof,

[0006] wherein one of Y and Z is N and the other is N, CH, or C-alkyl;

[0007] X is —O—, —S—, —SO—, —SO₂—, —NR⁶—, —CO—, —CH₂—, —CS—, —C(OR⁵)₂—,—C(SR⁵)₂—, —CONR²⁰—, —C(alkyl)₂-, —C(H)(alkyl)-, —NR²⁰—SO₂—, —NR²⁰CO—,

[0008] R is

[0009] hydrogen, acyl, alkyl, alkenyl, cycloalkyl, cycloalkylsubstituted with up to two alkyl groups, cycloalkenyl, bicycloalkyl,arylalkenyl, benzyl, benzyl substituted with up to three independentlyselected R³ groups, cycloalkylalkyl, polyhaloacyl, benzyloxyalkyl,hydroxyC₂-C₂₀alkyl, alkenylcarbonyl, alkylarylsulfonyl,alkoxycarbonylaminoacyl, alkylsutfonyl, or arylsulfonyl, additionally,when X is —CH₂—, R may also be —OH; in further addition, when X is notN, R may also be hydroxymethyl, in further addition, R and X may combineto form the group Prot-(NOAA)_(r)—NH— wherein r is an integer of 1 to 4,Prot is a nitrogen protecting group and when r is 1, NOAA is a naturallyoccuring amino acid or an enantiomer thereof, or when r is 2 to 4, eachNOAA is a peptide of an independently selected naturally occuring aminoacid or an enantiomer thereof;

[0010] R¹ and R²¹ are independently selected from the group consistingof alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, alkynyl,cyano, aminoalkyl, alkoxycarbonyl, aminocarbonyl, hydroxyguanidino,alkoxycarbonylalkyl, phenyl alkyl, alkylcarbonlyoxyalkyl,

[0011] H, —OH, (provided R¹ and R²¹ are both not —OH and Y is not N),formyl, —CO alkyl, —COacyl, —COaryl, and hydroxyalkyl; additionally R¹and R²¹ together may form the group

[0012] —CH₂, ═N—OR⁵, ═N—CN, ═N—N(R⁵)₂, ═CH-Alkyl, alkylene, =

[0013] ═C(halo)₂, in further addition, R¹ and R²¹ together with thecarbon atom to which they are attached may form the group

[0014] or R¹ and R²¹ together with the carbon atom to which they areattached may form a saturated heterocyclic ring containing 3 to 7 carbonatoms and one group selected from S, O, and NH;

[0015] R² is H, alkyl, alkenyl, cycloalkyl, cycloalkyl substituted with1 to 3 independently selected R³ groups, cycloalkenyl,hydroxyC₂-C₂₀alkyl, alkynyl, alkylamide, cycloalkylalkyl,hydroxyarylalkyl, bicycloalkyl, alkynyl, acylaminoalkyl, arylalkyl,hydroxyalkoxyalkyl, azabicyclo, alkylcarbonyl, alkoxyalkyl,aminocarbonylalkyl, alkoxycarbonylaminoalkyl,alkoxycarbonylamino(alkyl)alkyl; alkylcarbonyloxyalkyl,arylhydroxyalkyl, alkylcarbonylamino(alkyl)alkyl, dialkylamino,

[0016] (wherein q is an integer of 0 to 2)

[0017] wherein t is an integer of 3 to 5,

[0018] (wherein R²⁹ is H, alkyl, acyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl),

[0019] (wherein Q is O, NOH, or NO-alkyl), or when Z is —CH—, R² mayalso be alkoxycarbonyl, hydroxymethyl, —N(R⁸)₂;

[0020] R³, R⁴, R²², R²⁴, and R²⁵ are independently selected from thegroup consisting of H, halo, alkoxy, benzyloxy, benzyloxy substituted bynitro or aminoalkyl, haloalkyl, polyhaloalkyl, nitro, cyano, sulfonyl,hydroxy, amino, alkylamino, formyl, alkylthio, polyhaloalkoxy, acyloxy,trialkylsilyl, alkylsulfonyl, arylsulfonyl, acyl, alkoxycarbonylalkylsulfinyl; —OCONH₂, —OCONH-alkyl, —OCON(alkyl)₂, —NHCOO-alkyl,—NHCO-alkyl, phenyl, hydroxyalkyl, or morpholino;

[0021] each R⁵ and R⁶ is independently selected from the groupconsisting of H and alkyl, provided that when X is C(OR⁵)₂ or C(SR⁵)₂,both R⁵ groups cannot be H, and in addition, when X is C(OR⁵)₂ orC(SR⁵)₂, the two R⁵ groups in X may be joined to form —(CH₂)_(p)-wherein p is an integer of 2 to 4;

[0022] R⁷ is independently selected from the group consisting of H,alkyl, arylalkyl, cycloalkyl, aryl and aryl substituted with R³ and R⁴as defined herein;

[0023] each R⁸ is independently selected from the group consisting of H,hydroxyalkyl, or alkyl or two R⁸ groups may be joined to form analkylene group;

[0024] R⁹ is H, alkyl, or acyl:

[0025] R²⁰ is H, phenyl or alkyl; and

[0026] R²⁷ and R²⁸ are independently selected from the group consistingof H, alkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl,alkylthioalkyl, carboxyalkyl, imidazolyalkyl, and indolyalkyl,additionally R²⁷ and R²⁸ may combine to form an alkylene group.

[0027] In a preferred group of compounds Y and Z are N

[0028] In another preferred group of compounds Y is CH and Z is N

[0029] In another preferred group of compounds R is

[0030] and X is O, SO or SO₂.

[0031] In another preferred group of compounds R³ and R⁴ are H andeither R¹ is cycloalkyl, alkyl, or CN and R²¹ is H or R¹ and R²¹together form ═CH₂ or ═O.

[0032] In another preferred group of compounds R is

[0033] X is O, SO or SO₂, R³ and R⁴ are H and either R¹ is cycloalkyl,alkyl, or CN and R²¹ is H or R¹ and R²¹ together form ═CH₂ or ═O.

[0034] In another preferred group of compounds Y and Z are N, R¹ iscycloalkyl, alkyl or CN, R²¹ is H and R² is cycloalkyl or

[0035] In another preferred group of compounds Y is CH, Z is N, and R²is cycloalkyl or

[0036] In another preferred group of compounds at least one of R²⁷ andR²⁸ is alkyl.

[0037] In another preferred group of compound one of R²⁷ or R²⁸ ismethyl and the other is hydrogen.

[0038] In another preferred group of compounds R is

[0039] Another preferred group of compounds is the group represented bythe formula

[0040] wherein R, X, R¹, R^(27,) and R²¹ are as defined in the followingtable # from table of com- pounds R X R¹ R²¹ R²⁷ 169 4(CH₃O)—C₆H₄ SO CNH H iso A 227(−) 2-pyrimidinyl O cyclohexyl H H 289 4(CH₃O)—C₆H₄ SO CNCH₃ H 269 2-pyrimidinyl O CH₃ H CH₃ 214 4(CH₃O)—C₆H₄ SO₂ CO₂CH₃ H H 2322-pyrimidinyl O i-propyl H H 123 4(CH₃O)—C₆H₄ SO CH₃ H H 2364(CH₃O)—C₆H₄ SO

H H 296 4-(CH₃O)—C₆H₄ SO CH₃ CO₂Me H

[0041] or having the structural formula

[0042] Another group of preferred compounds of formula I are:

[0043] (in the table that follows, when R² is substituted cyclohexyl,the substituent positions are numbered as follows:

compound # 600 601 602 603 604 R

CH₃ 4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ R¹ CH₃ CH₃ CH₃ CH₃COOCH₃ R² cyclohexyl chex chex chex chex (chex) R³ H H 2-Cl H H R⁴ H H HH H R²¹ CH₃ H H H H R²⁷ H H H H H R²⁸ H H H H H X

SO SO SO Y N N N CH N Z N N N N N comp. no. 605 606 607 608 609 610 611R

4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ *see below 4-(CH₃O) —C₆H₄ R¹ chex CH₃ CNCN CN CN CN R² chex chex chex chex chex chex chex R³ H H H H H H H R⁴ HH H H H H H R²¹ H H H H CH₃ H CH₃ R²⁷ H H H H H H H R²⁸ H H H H H H H XS SO₂ SO SO₂ SO S SO₂ Y N N N CH N N CH Z N N N N N N N comp. no. 612613 614 615 616 617 R

4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ C₆H₅ *see below R¹ CH₃ CNCN CN CN CN R² chex chex chex chex chex chex R³ H H H H H H R⁴ H H H H HH R²¹ H H H CH₃ H H R²⁷ H (S)-3-CH₃ H H H H R²⁸ H H H H H H X SO₂ SO SOSO

SO Y N N CH N N N Z N N N N N N comp. no. 618 619 620 621 622 623 R C₆H₅*see below 2-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄

R¹ CH₃ CH₃ CN

CN (R)-CH₃ R² chex chex chex chex chex chex R³ H H H H H H R⁴ H H H H HH R²¹ CH₃ H H H H H R²⁷ H H H H (R)-2-CH₃ 2-CH₃ R²⁸ H H H H H H X O SO₂O SO SO₂ O Y N N N N N N Z N N N N N N comp. no. 624 625 626 627 628 629R *see below 4-(CH₃O) —C₆H₄ *see below *see below 4-(CH₃O) —C₆H₄

R¹ CN —CN CN CN CN CH₃ R² chex

chex chex chex chex R³ H H H H H H R⁴ H H H H H H R²¹ H H H H H H R²⁷ HH H H (R)-2-CH₃ (R)-2-CH₃ R²⁸ H H H H H H X S S S SO SO O Y N N N N N NZ N CH N N N N comp. no. 630 631 632 633 634 635 R *see below *see below4-(CH₃O) 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ R¹ CN CNwith R²¹ forms = O CN CN

R² chex chex chex

chex chex R³ H H H H H H R⁴ H H H H H H R²¹ H H — H H H R²⁷ H H H H(R)-2-CH₃ H R²⁸ H H H H H H X SO SO S SO S SO Y N N CH N N N Z N N N CHN N comp. no. 636 637 638 639 640 641 R

4-(CH₃O) —C₆H₄ chex 4-(HO) —C₆H₄ 4-(CH₃O) —C₆H₄ R¹ with R²¹ CN with R²¹CN CN with R²¹ forms = O forms = O forms = N—OCH₃ R² chex chex chex chexchex chex R³ H H H H H H R⁴ H H H H H H R²¹ — H — H H — R²⁷ H (R)-2-CH₃H H H H R²⁸ H H H H H H X S SO₂ SO₂ SO₂ S SO Y CH N CH N N CH Z N N N NN N comp. no. 642 643 644 645 646 647 R C₆H₅ 4-(CH₃O) 4-(CH₃O) chex4-(CH₃O) 4-(CH₃O) —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ R¹ (S)-CH₃ CN CN CN withR²¹forms = O with R²¹forms =N—OCH₃ R² chex chex chex chex chex chex R³ HH H H H H R⁴ H H H H H H R²¹ H H H H — — R²⁷ (R)-2-CH₃ (S)-2-CH₃ H H H HR²⁸ H H H H H H X SO₂ SO₂ C═O SO SO SO Y N N CH N CH CH Z N N N N N Ncomp. no. 648 649 650 651 652 653 R C₆H₅ chex 4-(CH₃O) C₆H₅ 4-(CH₃O)4-(CH₃O) —C₆H₄ —C₆H₄ —C₆H₄ R¹ (R)-CH₃ CN CN with R²¹ with R²¹ CH₃ forms= O forms = O R² chex chex chex chex chex chex R³ H H H H H H R⁴ H H H HH H R²¹ H H H — — — R²⁷ (R)-2-CH₃ H (R)-2-CH₃ H H (R)-2-CH₃ R²⁸ H H H HH H X SO₂ S SO S SO S Y N N N CH CH N Z N N N N N N comp. no. 654 655656 657 658 659 R C₆H₅ 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) 4-(F)-C₆H₄—C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ R¹ with R²¹ CN (R)-CH₃ with R²¹ forms CN withR²¹ forms = CH₂

forms = CH₂ R² chex chex chex chex

chex R³ H H H H H H R⁴ H H H H H H R²¹ — CH₃ H — H — R²⁷ H H (R)-2-CH₃ HH H R²⁸ H H H H H H X SO SO SO₂ SO SO SO Y CH CH N CH N CH Z N N N N CHN comp. no. 660 661 662 663 664 665 R C₆H₅ 4-(CH₃O) —C₆H₄ 4-(F)-C₆H₄4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄

R¹ with R²¹ —CONH₂ with R²¹ with R²¹ —COOCH₃ with R²¹ forms = O forms =O forms = CH₂ forms = O R² chex chex chex chex

chex R³ H H H H H H R⁴ H H H H H H R²¹ — H — — H — R²⁷ H H H H H H R²⁸ HH H H H H X SO₂ SO SO₂ SO₂ SO S Y CH CH CH CH N CH Z N N N N CH N comp.no. 666 667 668 669 670 671 R C₆H₅ 4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄4-(CH₃O) —C₆H₄ 4-(F)-C₆H₄

R¹ with R²¹ (S)-CH₃ —COOCH₃ with R²¹ with R²¹ with R²¹ forms = forms =CH₂ forms = N—OH forms = O O R² chex chex chex chex chex chex R³ H H H HH H R⁴ H H H H H H R²¹ — H H — — — R²⁷ H (R)-2-CH₃ H H H H R²⁸ H H H H HH X SO₂ SO₂ SO SO SO SO Y CH N CH CH CH CH Z N N N N N N comp. no. 672673 674 675 676 677 R 4-(CH₃O) —C₆H₄

4-(CH₃O) —C₆H₄

4-(CH₃O) —C₆H₄

R¹ —CF₃ with R²¹ see note with R²¹ with R²¹ with R²¹ forms = forms =forms = forms = CH CH₂ CH₂ NOCH₃ Isomer A R² chex chex chex chex

chex R³ H H H H H H R⁴ H H H H H H R²¹ H — — — — — R²⁷ H H H H H H R²⁸ HH H H H H X SO S SO SO SO SO Isomer 1 Y N CH CH CH CH CH Z N N N N N Ncomp. no. 678 679 680 681 682 683 R 4-(CH₃O) —C₆H₄

4-(CH₃O) —C₆H₄

R¹ F₃C— with R²¹ with R²¹ with R²¹ with R²¹ with R²¹ forms = O forms = Oforms = CH₂ forms = CH₂ forms = O R² chex chex chex chex 4(C₆H₅)chexchex R³ H H H H H H R⁴ H H H H H H R²¹ H — — — — — R²⁷ H H H H H H R²⁸ HH H H H H X SO₂ SO SO₂ SO₂ SO S Y N CH CH CH CH CH Z N N N N N N comp.no. 684 685 686 687 688 689 R 4(F)C₆H₄ 4-(CH₃O) —C₆H₄

4-(CF₃) —C₆H₄ 4-(CH₃O) —C₆H₄

R¹ with R²¹ with R²¹ forms = CH₂ with R²¹ with R²¹ with R²¹ with R²¹forms = CH₂ forms = O forms = CH₂ forms = CH₂ forms = O R² chex

chex chex 4(C₆H₅)chex chex R³ H H H H H H R⁴ H H H H H H R²¹ — — — — — —R²⁷ H H H H H H R²⁸ H H H H H H X SO₂ S SO SO SO₂ SO₂ Y CH CH CH CH CHCH Z N N N N N N comp. no. 690 691 692 693 694 695 R

4-(CH₃O) —C₆H₄

3-(CH₃O) —C₆H₄ 2-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ R¹ with R²¹ —CN with R²¹with R²¹ with R²¹ —CH₃ forms = CH₂ forms = CH₂ forms = O forms = O R²chex chex chex chex chex chex R³ H H H H H H R⁴ H H H H H H R²¹ — H — —— —CH₃ R²⁷ H H H H H H R²⁸ H H H H H H X S SO SO SO₂ SO₂ SO₂ Y CH CH CHCH CH CH Z N N N N N N comp. no. 696 697 698 699 700 701 R 2-(CH₃O)—C₆H₄

4-benzyloxy phenyl 2-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ R¹ withR²¹ with R²¹ with R²¹ with R²¹ with R²¹ with R²¹ forms = CH₂ forms = Oforms = CH₂ forms = O forms = O forms = O R² chex chex chex chex chexchex R³ H H H H H H R⁴ H H H H H H R²¹ — — — — — — R²⁷ H H H H 2-(CH₃) HR²⁸ H H H H H H X O SO SO₂ S SO₂ SO₂—NH Y CH CH CH CH CH CH Z N N N N NN comp. no. 702 703 704 705 706 707 R 4-(CH₃O) —C₆H₅

3-(CH₃O) —C₆H₅ 4-(CH₃O) —C₆H₅ 4-(CH₃O) —C₆H₅ 4-(CH₃O) —C₆H₅ R¹ —CN withR²¹ with R²¹ —CH₃ with R²¹ (S)-C₂H₅ forms = CH₂ forms = O forms = CH₂ R²chex chex chex chex chex chex R³ H H H H H H R⁴ H H H H H H R²¹ H — ——CH₃ — H R²⁷ H H H H 2(CH₃) (R)-2-(CH₃) R²⁸ H H H H H H X SO SO₂ SO SOSO₂ SO₂ Y CH CH CH CH CH CH Z N N N N N N comp. no. 708 709 710 711 712713 R 4-(CH₃O) 4-(CH₃O) 3-(Cl)-C₆H₄ 4(-CH₃O) see note 712. 4-(CH₃O)—C₆H₄ —C₆H₅ —C₆H₄ —C₆H₄ R¹ (R)-C₂H₅ with R²¹ CH₃ with R²¹ forms = CH₂with R²¹ —CN forms = O forms = O R² chex chex

chex chex R³ H H H H H H R⁴ H H H H H H R²¹ H — H — — —CH₃ R²⁷(R)-2-(CH₃) H H H H H R²⁸ H H H H H H X SO₂ SO₂ SO₂ SO₂ SO₂ SO₂ Y N CH NCH CH CH Z N N N N N N comp. no. 714 715 716 717 718 719 R 4-CH₃O)4-(CH₃O) 4-(HO) 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄—C₆H₄ R¹ (S)-2- —CH₃ with R²¹ with R²¹ with R²¹ with R²¹ propyl isomer 1forms = O forms = CH₂ forms = O forms = O R² chex chex chex

chex

R³ H H H H H H R⁴ H H H H H H R²¹ H H — — — — R²⁷ (R)-2(CH₃)(R)-2-n-C₃H₇ H H H H R²⁸ H H H H H H X SO₂ SO₂ SO₂ SO₂ —CONH— SO₂ Y N NCH CH CH CH Z N N N N N N comp. no. 720 721 722 723 724 725 R4-(CH₃P)—C₆H₄ 4-(CH₃O) —C₆H₄ 4-(CF₃O) —C₆H₄

4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ R¹ (R)-2-propyl CH₃ with R²¹ with R²¹forms = O —CH₃ with R²¹ forms = O isomer 2 forms = O R² chex chex chexchex chex

R³ H H H H H H R⁴ H H H H H H R²¹ H H — — —CN — R²⁷ (R)-2(CH₃) (R)-2-n-H H H H propyl R²⁸ H H H H H H X SO₂ SO₂ SO₂ SO₂ SO₂ SO Y N N CH CH CHCH Z N N N N N N comp. no. 726 727 728 729 730 731 R 4-(CH₃O) 4-(CH₃O)4-(CH₃O) 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄R¹ (S)-CH₃ (S)-CH₃ (S)-CH₃ CH₃ with R²¹ (S)-CH₃ forms = O R² cyclopentylcycloheptyl cyclobutyl

chex cyclopropyl R³ H H H H H H R⁴ H H H H H H R²¹ H H H H — H R²⁷(R)-2-(CH₃) 3-(CH₃) (R)-2-(CH₃) H (R)-2-(CH₃) (R)-2-(CH₃) R²⁸ H H H H HH X SO₂ SO₂ SO₂ SO SO₂ SO₂ Y N N N N N N Z N N N CH N N comp. no. 732733 734 735 736 737 R 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) 4-(CH₃O)4-(CH₃O) —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ R¹ (S)-CH₃ (S)-CH₃ (S)-CH₃CH₃ (S)-CH₃ (S)-CH₃ R² cyclopentyl cyclooctyl cyclobutyl

cyclopropyl R³ H H H H H H R⁴ H H H H H H R²¹ H H H H H H R²⁷ 3(CH₃)(R)-2(CH₃) 3(CH₃) H (R)-2(CH₃) 3(CH₃) R²⁸ H H H H H H X SO₂ SO₂ SO₂ SO₂SO₂ SO₂ Y N N N N N N Z N N N CH N N comp. no. 738 739 740 741 742 743 R3-(CH₃O) 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) 44-(CH₃O) See note —C₆H₄ —C₆H₄ —C₆H₄—C₆H₄ —C₆H₄ 743 R¹ (S)-CH₃ (S)-CH₃ with R²¹ (S)-CH₃ (S)-CH₃ CH₃ forms =CH₂ R² cycloheptyl cyclooctyl chex chex

chex R³ H H H H H H R⁴ H H H H H H R²¹ H H — H H H R²⁷ (R)-2(CH₃) 3(CH₃)with R²⁸ forms 3-(CH₃) 3-(CH₃) H 3,5-(CH₂)₂— R²⁸ H H — H H H X SO₂ SO₂SO₂ SO₂ SO₂ —CONH— Y N N CH N N N Z N N N N N N comp. no. 744 745 746747 748 749 R See Note See Note See Note See Note 4(-CH₃O) See Note—C₆H₄ R¹ CH₃ CH₃ CN CH₃ —OH CH₃ R² chex chex chex chex chex chex R³ H HH H H H R⁴ H H H H H H R²¹ H H H H H H R²⁷ H H H H H H R²⁸ H H H H H H X—CONH— —CONH— S O SO —CONH— Y N N N N CH N Z N N N N N N comp. no. 750751 752 753 754 755 R See Note See Note See Note 4-(CH₃O) —C₆H₄

4-(CH₃O) —C₆H₄ R¹ CH₃ CH₃ CN

with R²¹ forms = O with R²¹ forms = O R² chex chex chex chex chex chexR³ H H H H H H R⁴ H H H H H H R²¹ H H H H — — R²⁷ H H H H H 1-(CH₃) R²⁸H H H H H H X —CONH— —CONH— SO₂ SO SO SO Y N N N N CH CH Z N N N N N Ncomp. no. 756 757 758 759 760 761 R 4-(CH₃O) —C₆H₄

4-(CH₃O) —C₆H₄

4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ R¹ OH with R²¹ forms = O —CH₃OH OH withR²¹ forms = CH₂ OH R² chex chex chex chex

chex R³ H H H H H H R⁴ H H H H H H R²¹ 2-propyl — H CH₃ — ethyl R²⁷ H HH H H H R²⁸ H H H H H H X SO SO S SO SO₂ SO Y CH CH CH CH CH CH Z N N NN N N comp. no. 762 763 764 765 766 767 R

4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ 4-(CH₃O)—C₆H₄ R¹ with R²¹ forms = CH₂ with R²¹ forms = CH₂

with R²¹ forms = CH₂ —CH₂—OH —CH₂—OH R² chex

chex

chex chex R³ H H H H H H R⁴ H H H H H H R²¹ — — H — H H R²⁷ H H H H H HR²⁸ H H H H H H X SO SO S S SO₂ SO Y CH CH CH CH CH CH Z N N N N N Ncomp. no. 768 769 770 771 772 773 R

4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ 4-(CH₃O)—C₆H₄

R¹ with R²¹ forms = —CH₂—OC—O with R²¹ CH₃ with R²¹ forms = with R²¹forms = N—OCH₃ CH₃ forms = CF₂ N—OCH₃ N—OCH₃ Isomer B Isomer A Isomer BR² chex chex chex

chex chex R³ H H H H H H R⁴ H H H H H H R²¹ — H — H — — R²⁷ H H H H H HR²⁸ H H H H H H X SO Isomer 2 SO SO₂ SO₂ SO Isomer 2 SO Isomer 1 Y CH CHCH CH CH CH Z N N N N N N comp. no. 774 775 776 777 778 R 4-(CH₃O)4-(CH₃O) 4-(CH₃O) 4-(CH₃O) omit —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ R¹ CH₃—O—CO—with R²¹ with R²¹ forms = CF₂ CH₃ CH₃ forms = CH₂ R² chex chex

R³ H H H H R⁴ H H H H R²¹ H — — H R²⁷ H H H (R)-2(CH₃) R²⁸ H H H H X SO₂SO SO₂ SO₂ Y CH CH CH CH Z N N N N comp. no. 779 780 781 782 783 R4-(CH₃O) 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄—C₆H₄ R¹ n-butyl (CH₃)₂—C₆H₄ with R²¹ forms = with R²¹ forms = (S)-CH₃isomer 1 isomer 1 CH₂ CH₂ R² chex chex

R³ H H H H H R⁴ H H H H H R²¹ H H — — H R²⁷ (R)-2-(CH₃) (R)-2-CH₃ H H(R)-2-CH₃ R²⁸ H H H H H X SO₂ SO₂ SO₂ S SO₂ Y N N CH CH N Z N N N N Ncomp. no. 784 785 786 787 788 R 4-(CH₃O) 4-(CH₃O) 4-(CH₃O) 4-(CH₃O)4-(CH₃O) —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ —C₆H₄ R¹ n-butyl —(CH₂)₃ cyclopentylwith R²¹ forms = CH₂ (S)-CH₃ isomer 2 —C₆H₅ isomer 1 isomer 2 R² chexchex chex

R³ H H H H H R⁴ H H H H H R²¹ H H H — H R²⁷ (R)-2-CH₃ (R)-2-CH₃(R)-2-CH₃ H (R)-2-CH₃ R²⁸ H H H H H X SO₂ SO₂ SO₂ SO SO₂ Y N N N CH N ZN N N N N comp. no. 789 790 791 792 793 R 4-(CH₃O) 4-(CH₃O) 4-(CH₃O)(see 4-(CH₃O) —C₆H₄ —C₆H₄ —C₆H₄ (note —C₆H₄ 792)- R¹ (S)-CH₃ (R)-2-CH₃(S)-CH₃ CN (S)-CH₃ R²

chex H R³ H H H H H R⁴ H H H H H R²¹ H H H H H R²⁷ (R)-2-(CH₃) (R)-2-CH₃(R)-2-CH₃ H (R)-2-CH₃ R²⁸ H H H H H X S S SO₂ SO SO₂ Y N N N N N Z N N NN N comp. no. 794 795 796 797 798 R 4-(CH₃O) —C₆H₄

4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ R¹ (S)-CH₃ (R)-CH₃ (S)-CH₃(S)-CH₃ CH₃ R²

chex

1-CH₃-chex R² H H H H H R⁴ H H H H H R²¹ H H H H H R²⁷ (R)-2-(CH₃)(R)-2-(CH₃) (R)-2-(CH₃) (R)-2-CH₃ H R²⁸ H H H H H X SO₂ SO₂ S SO₂ SO₂ YN N N N N Z N N N N N comp. no. 799 800 801 802 803 R 4-(CH₃O) —C₆H₄4-(CH₃O) —C₆H₄

4-(CH₃O) —C₆H₄ 4-(CH₃O) —C₆H₄ R¹ (R)-CH₃ CH₃ (S)-CH₃ CH₃ (S)-CH₃ R²

chex chex chex 4-(OH)-chex R³ H H H H H R⁴ H H H H H R²¹ H CH₃ H CH₃ HR²⁷ (R)-2-CH₃ 2-CH₃ (R)-2-CH₃ 2-CH₃ 3-CH₃ R²⁸ H H H H H X SO₂ SO₂ SO₂ SSO₂ Y N CH N CH N Z N N N N N comp. no. 804 805 R 4-(CH₃O) —C₆H₄

R¹ (S)-CH₃ (S)-CH₃ R² trans 4-(OH)-chex

R³ H H R⁴ H H R²¹ H H R²⁷ (R)-2-(CH₃) (R)-2-CH₃ R²⁸ H H X SO₂ SO₂ Y N NZ N N *610. R is

*617. R is

*619. R is

*624. R is

626 and 627 R is

*630. R is

*631. R is

674. R¹ and R²¹ together with the carbon atom to which they are attachedfrom

712. R is

743. R is

744. R is

745. R is

746. R. is 4-[CH₃—N(CH₃)—COO]—C₆H₄ 747. R is

749. R is

750 R is

751. R is

752. R is 4-[(CH₃)₂N—COO]—C₆H₄— 792. R is 4-[(CH₃)₂NCOO]-C₆H₄—

[0044] Another aspect of the invention is a pharmaceutical compositionwhich comprises a compound having structural formula I as defined abovein combination with a pharmaceutically acceptable carrier.

[0045] Another aspect of the invention is the use of a compound formulaI for the preparation of a pharmaceutical composition useful in thetreatment of cognitive disorders and neurodegenerative diseases such asAlzheimer's disease.

[0046] Yet another aspect of the invention comprises a method for makinga pharmaceutical composition comprising mixing a compound of formula Iwith a pharmaceutically acceptable carrier.

[0047] Another aspect of this invention is a method for treating acognitive or neurodegenerative disease comprising administering to apatient suffering from said disease an effective amount of a compound offormula I.

[0048] Another aspect of this invention is a method for treatingcognitive and neurodegenerative diseases, such as Alzheimer's diseasewith a compound of formula I in combination with an acetylcholinesteraseinhibitor.

[0049] Another aspect of this invention is a method for treating acognitive or neurodegenerative disease comprising administering to apatient suffering from said disease an effective amount of a combinationof a compound capable of enhancing acetylcholine release (preferably anm2 or m4 selective muscarinic antagonist) with an acetycholinesteraseinhibitor.

[0050] Another aspect of this invention is a kit comprising in separatecontainers in a single package pharmaceutical compounds for use incombination to treat cognitive disorders in one container a compound offormula I or a compound capable of enhancing acetylcholine release(preferably an m2 or m4 selective muscarinic antagonist) in apharmaceutically acceptable carrier and in a second container anacetylcholinesterase inhibitor in a pharmaceutically acceptable carrier,the combined quantities being an effective amount.

BRIEF DESCRIPTION OF THE DRAWINGS

[0051]FIG. 1 illustrates the dose related effects of i.p. administrationof a compound of this invention on acetyIchioline (ACh) release fromcortex of conscious rat.

[0052]FIG. 2 is a plot similar to FIGS. 1 for ACh release from thestriatum following i.p. administration.

[0053]FIG. 3 illustrates the effect of 3 mg/kg of Tacrine (i.p.administration) on ACh release from striatum of conscious rat.

[0054]FIG. 4 is a plot similar to FIG. 4 for 1 mg/kg of a compound ofthis invention (i.p. administration).

[0055]FIG. 5 is a plot similar to FIG. 4 for 1 mg/kg of a compound ofthis invention in combination with 3 mg/kg of Tacrine (both i.p.administration).

DETAILED DESCRIPTION

[0056] Except where stated otherwise the following definitions applythroughout the present specification and claims. These definitions applyregardless of whether a term is used by itself or in combination withother terms. Hence the definition of “alkyl” applies to “alkyl” as wellas the “alkyl” portions of “alkoxy”, “haloalkyl”, etc.

[0057] Alkyl represents a straight or branched saturated hydrocarbonchain having 1 to 20 carbon atoms, more preferably 1 to 8 carbon atoms.

[0058] Alkenyl represents a straight or branched hydrocarbon chain offrom 2 to 15 carbon atoms, more preferably 2 to 12 carbon atoms, havingat least one carbon-to-carbon double bond.

[0059] Alkynyl represents a straight or branched hydrocarbon chain offrom 2 to 10 carbon atoms, more preferably 2 to 8 carbon atoms, havingat least one carbon-to-carbon triple bond.

[0060] Cycloalkyl represents a saturated carbocyclic ring having 3 to 12carbon atoms.

[0061] Cycloalkenyl represents a carbocyclic ring having from 5 to 8carbon atoms and at least one carbon-to-carbon double bond in the ring.

[0062] Bicycloalkyl represents a saturated bridged carbocyclic ringhaving 5 to 12 carbon atoms.

[0063] Acyl represents a radical of the formula

[0064] wherein alkyl is as defined previously.

[0065] Halo represents fluoro, chloro, bromo or iodo.

[0066] Aryl represents phenyl of naphthyl.

[0067] Polyhalo represent substitution of at least 2 halo atoms to thegroup modified by the term “polyhalo”.

[0068] Hydroxyguanidino represents a group having the formula

[0069] Azabicyclo represents a saturated bridged ring containing from 4to 8 carbon atoms and at least one nitrogen atom.

[0070] Sulfonyl represents a group of the formula —SO₂—.

[0071] Sulfinyl represents a group of the formula —SO—.

[0072] Alkylene represents a group having the formula —(CH₂)_(q),wherein q is an integer of from 1 to 20,

[0073] Naturally occurring amino acid (NOAA) means an acid selected fromthe group consisting of alanine(ala), arginine (arg), asparagine (asn),aspartic acid (asp), cysteine (cys), glutamine (gin), glutamic acid(glu), glycine (gly), histadine (his), isoleucine (ile), leucine (leu),lysine (lys), methionine (met), phenylalanine (phe), proline (pro),serine (ser), threonine (thr), tryptophan (trp), tyrosine (tyr), andvaline (val).

[0074] Nitrogen protecting group (Prot) means a group capable ofprotecting a nitrogen on a naturally occurring amino acid (or anenantiomer thereof) from reaction. Preferred nitrogen protecting groupsare carbobenzyloxy (CBZ), CH₃OCO(CH₂)₉CO, and t-butcyxycarbonyl. Ofcourse any operable nitrogen protecting group is included.

[0075] When a variable appears more than once in the structural formula,for example R⁵ when X is —C(OR⁵)₂—, the identity of each variableappearing more than once may be independently selected from thedefinition for that variable.

[0076] Compounds of this invention may exist in at least two stereoconfigurations based on the asymmetric carbon to which R¹ is attached,provided that R¹ and R²¹ are not identical. Further stereoisomerism ispresent when X is SO, or C(OR⁵)₂ (when the two R⁵ groups are not thesame) or when R is —CR⁵═C═CR⁶. Also within formula I there are numerousother possibilities for stereoisomerism. All possible stereoisomers offormula I are within the scope of the invention.

[0077] Compound of formula I can exist in unsolvated as well as solvatedforms, including hydrated forms. In general, the solvated forms, withpharmaceutically acceptable solvents such as water, ethanol and thelike, are equivalent to the unsolvated forms for purposes of thisinvention.

[0078] A compound of formula I may form pharmaceutically acceptablesalts with organic and inorganic acids. Examples of suitable acids forsalt formation are hydrochloric, sulfuric, phosphoric, acetic, citric,malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic and other mineral and carboxylic acids well known tothose skilled in the art. The salts are prepared by contacting the freebase forms with a sufficient amount of the desired acid to produce asalt in the conventional manner. The free basis forms may be regeneratedby treating the salt with a suitable dilute aqueous base solution suchas dilute aqueous sodium hydroxide, potassium carbonate, ammonia orsodium bicarbonate. The free base forms differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the salts are otherwise equivalent to theirrespective free base forms for purposes of the invention.

[0079] Compound in accordance with formula I may be produced byprocesses known to those skilled in the art as shown by the followingreaction steps:

[0080] Process A (for compounds of formula I where R²¹ is H and X is O,SO, or SO₂)

[0081] wherein L¹ is a leaving group and L² is H or an alkali metal andY, Z, R, R¹, R², R³, R⁴, R²⁷ and R²⁸ are as defined above for formula I,and X is O, SO or SO₂.

[0082] Process A is preferably carried out neat or in a solvent such asDMF, DMSO, or acetonitrile, at temperatures, ranging from 0° C. to 110°C. for a period of about 1-24 hours. It is preferable that L¹ be achloride leaving group, but other leaving groups such as bromide, ormesylate, will suffice. It is preferable that L² be hydrogen.

[0083] Starting materials of formula II when X is O, SO, or SO₂ may beformed by the following reaction sequence

[0084] In step (a) the chloride compound is reacted with sodiumhydroxide in presence of zinc in solvent such as water, at 50-95° C. for1-3 hours. Alternatively R—X—H is reacted with NaH in solvent such asTHF or DMF at 0° to room temperature for 1-3 hours. In step (b) thesubstituted benzaldehyde is added to the reaction mixture from step (a)and the reaction carried out for 1-24 hours at 20-70° C. In step (c) X²represents e.g. chloride or bromide. The reaction with R¹MgX² is carriedout in THF or diethyl ether solvent at 0° C. -70° C. for 1-24 hours.Reaction with SOCl₂ is preferably done in excess thionyl chloride assolvent at 25-70° C. for 1-24 hours. Compounds of formula III arereadily available. Some reaction schemes for making other compounds offormula II are shown below:

[0085] wherein L⁴ is a leaving group and L² is H or alkali metal and X,Y, Z, R, R¹, R², R³, R⁴, R²¹, R²⁷ and R²⁸ are as defined above forformula I.

[0086] Process B is preferably carried out in solvent such as DMF atabout 25 to 120° C. for about 1-24 hours. It is preferred that L² be Naor hydrogen and that L⁴ be a chloride leaving group.

[0087] Compounds of formula IV may be produced by the following reactionscheme:

[0088] In the above reactions scheme R^(1A) is preferably in accordancewith the definition of R⁷ for formula I.

[0089] Step (d) may be performed in acetone or DMF solvent at 20-100°C., for 1-24 hours under basic conditions, e.g. with K₂CO₃.

[0090] Step (e) may be performed neat or in methylene chloride, at20-70° C., for 1-24 hours.

[0091] Step (f) may be performed in ethanol or methanol at 25-70° C. for1-24 hours.

[0092] Process C (for compounds of formula I where R²¹ is H)

[0093] wherein L⁶ is a leaving group and L² is H or alkali metal and X,Y, Z, R, R¹, R², R³, R⁴, R²⁷ and R²⁸ are as defined above for formula I.

[0094] Process C is preferably carried out in solvent such as DMF, DMSOor acetonitrile at about 0 to 110° C. for 1-24 hours. It is preferablethat L² be hydrogen and that L⁶ be a chloride leaving group.

[0095] Compounds of formula VI may be produced by the following reactionscheme:

[0096] Other compounds of formula VI may be produced by similarreactions.

[0097] Process D (for compounds of formula I where R²¹ is H)

[0098] werein Y¹ is H or alkyl, and compound X is (alkyl)₂AlCN or aGrignard reagent.

[0099] Process D is preferably carried out by first treating a compoundof formula VIII, titanium tetrachloride (TiCl₄) or titanium tetraisopropoxide, and a compound of formula IX neat or in solvent such asmethylene chloride for about 1-24 hours at 20 to 70° C. Finally acompound of formula X is added and the mixture is stirred for 1-24 hoursat 20-70° C. Compounds of formula VIII may be produced by steps (a) and(b) of process A.

[0100] Process E (for compounds wherein R²¹ is not H)

[0101] In the above reaction L is a leaving group. the reaction isperformed insolvent, e.g. THF, at −70 C to room temperature for ½ to 12hours.

[0102] Process F (for compounds of structure XI or XII when Y and Z areboth N, especially for non-racemic compounds where R¹ and R²⁷ are bothCH₃)

[0103] Reagents: a: (CF₃CO)₂O; b: dibromodimethylhydantoin, CH₃SO₃H; c:MeLi, then n-Buli, then RSO₂F; d: NaOH; e: R₂₇CH(OSO₂CF₃)CO₂Et, K₂CO₃;f: ICH₂CO₂Et, Na₂CO₃; g: LiAlH₄; h: AcOCH₂COCl; i: BH₃.Me₂S.

[0104] Reaction of diol (8) with thionyl chloride gives a mixture ofchlorides (10), which are in equilibrium with each other. This mixtureis reacted with primary amines to afford compounds of the invention (11)and (12).

[0105] When the starting material 1 and reagent R₂₇CH(OSO₂CF₃)CO₂Et areoptically pure or enriched, the products 11 and 12 are non-racemic.

[0106] Process G

[0107] For compounds of formula I where R¹ is alkyl, R²¹ is H, and Y isN, especially compounds of this type when X is SO₂ and the carbon towhich R¹ and R²¹ are attached is not racemic.

[0108] The above reactions may be followed if necessary or desired byone or more of the following steps; (a) removing any protective groupsfrom the compound so produced; (b) converting the compound so-producedto a pharmaceutically acceptable salt, ester and/or solvate; (c)converting a compound in accordance with formula I so produced toanother compound in accordance with formula I, and (d) isolating acompound of formula I, including separating stereoisomers of formula I.

[0109] Based on the foregoing reaction sequence, those skilled in theart will be able to select starting materials needed to produce anycompound in accordance with formula I.

[0110] In the above processes it is sometimes desirable and/or necessaryto protect certain groups during the reactions. Conventional protectinggroups, familiar to those skilled in the art, are operable. After thereaction or reactions, the protecting groups may be removed by standardprocedures.

[0111] The compounds of formula I exhibit selective m2 and/or m4muscarinic antagonizing activity, which has been correlated withpharmaceutical activity for treating cognitive disorders such asAlzheimers disease and senile dementia.

[0112] The compounds of formula I display pharmacological activity intest procedures designated to indicate m1 and m2 muscarinic antagonistactivity. The compounds are non-toxic at pharmaceutically therapeuticdoses. Following are descriptions of the test procedures.

MUSCARINIC BINDING ACTIVITY

[0113] The compound of interest is tested for its ability to inhibitbinding to the cloned human m1, m2, m3, and m4 muscarinic receptorsubtypes. The sources of receptors in these studies were membranes fromstably transfected CHO cell lines which were expressing each of thereceptor subtypes. Following growth, the cells were pelleted andsubsequently homogenized using a Polytron in 50 volumes cold 10 mM Na/Kphosphate buffer, pH 7.4 (Buffer B). The homgenates were centrifuged at40,000×g for 20 minutes at 4° C. The resulting supernatants werediscarded and the pellets were resuspended in Buffer B at a finalconcentration of 20 mg wet tissue/ml. These membranes were stored at−80° C. until utilized in the binding assays described below.

[0114] Binding to the cloned human muscarinic receptors was performedusing ³H-quinuclidinyl benzilate (QNB) (Watson et al., 1986). Briefly,membranes (approximately 8, 20, and 14 μg of protein assay for the m1,m2, and m4 containing membranes, respectively) were incubated with³H-QNB (final concentration of 100-200 pM) and increasing concentrationsof unlabeled drug in a final volume of 2 ml at 25° C. for 90 minutes.Non-specific binding was assayed in the presence of 1 μM atropine. Theincubations were terminated by vacuum filtration over GF/B glass fiberfilters using a Skatron filtration apparatus and the filters were washedwith cold 10 mM Na/K phosphate butter, pH 7.4. Scintillation cocktailwas added to the filters and the vials were incubated overnight. Thebound radioligand was quantified in a liquid scintillation counter (50%efficiency). The resulting data were analyzed for IC₅₀ values (i.e. theconcentration of compound required to inhibit binding by 50%) using theEBDA computer program (McPherson, 1985). Affinity values (K_(i)) werethen determined using the following formula (Cheng and Prusoff, 1973);$K_{i} = \frac{{IC}_{50}}{1 + \left\lbrack \frac{{concentration}\quad {of}\quad {radioligand}}{{affinity}\quad \left( K_{D} \right)\quad {of}\quad {radioligand}} \right\rbrack}$

[0115] Hence a lower value of K_(i) indicates greater binding affinity.

[0116] The following publications, the entire contents of which areincorporated herein by reference, explain the procedure in more detail.

[0117] Cheng, Y. -C. and Prusoff, W. H., Relationship between theinhibitory constant (K_(i)) and the concentration of inhibitor whichcauses 50 per cent inhibition (IC₅₀) of an enzymatic reaction. Biochem.Pharmacol. 22: 3099-3108, 1973.

[0118] McPherson, G. A. Kinetic, EBDA, Ligand, Lowry: A Collection ofRadioligand Binding Analysis Programs. Elsevier Science Publishers BV,Amsterdam, 1985.

[0119] Watson, M. J, Roeske, W. R. and Yamamura, H. I. [³H] Pirenzepineand (−)[³H)quinuclidinyl benzilate binding to rat cerebral cortical andcardiac muscarinic cholinergic sites. Characterization and regulation ofantagonist binding to putative muscarinic subtypes. J. Pharmacol. Exp.Ther. 237: 411-418, 1986.

[0120] To determine the degree of selectivity of a compound for bindingthe m2 receptor, the K_(i) value for m1 receptors was divided by theK_(i) value for m2 receptors. A higher ratio indicates a greaterselectivity for binding the m2 muscarinic receptor.

MICRODIALYSIS METHODOLOGY

[0121] The following procedure is used to show that a compound functionsas an m2 antagonist.

[0122] Surgery: For these studies, male Sprague-Dawley Rats (250-350 g)were anesthetized with sodium pentobarbital (54 mg/kg, ip) and placed ona Kopf sterotaxic apparatus. The skull was exposed and drilled throughto the dura at a point 0.2 mm anterior and 3.0 mm lateral to the bregma.At these coordinates, a guide cannula was positioned at the outer edgeof the dura through the drilled opening, lowered perpendicularly to adepth of 2.5 mm, and permanently secured with dental cement to bonescrews. Following the surgery, rats were given ampicillin (40 mg/kg, ip)and individually housed in modified cages. A recovery period ofapproximately 3 to 7 days was allowed before the microdialysis procedurewas undertaken.

[0123] Microdialysis: All of the equipment and instrumentation used toconduct in vivo microdialysis was obtained from Bioanalytical Systems,Inc. (BAS). The microdialysis procedure involved the insertion throughthe guide cannula of a thin, needle-like perfusable probe (CMA/12,3mm×0.5 mm) to a depth of 3 mm in striatum beyond the end of the guide.The probe was connected beforehand with tubing to a microinjection pump(CMA-/100). Rats were collared, tethered, and, following probeinsertion, were placed in a large, clear, plexiglass bowl with littermaterial and access to food and water. The probe was perfused at 2μl/min with Ringer's buffer (NaCl 147 mM; KCl 3.0 mM; CaCl₂ 1.2 mM;MgCl₂ 1.0 mM) containing 5.5 mM glucose, 0.2 mM L-ascorbate, and 1 μMneostigmine bromide at pH 7.4). To achieve stable baseline readings,microdialysis was allowed to proceed for 90 minutes prior to thecollection of fractions. Fractions (20 μl) were obtained at 10 minuteintervals over a 3 hour period using a refrigerated collector (CMA/170or 200). Four to five baseline fractions were collected, following whichthe drug or combination of drugs to be tested was administered to theanimal. Upon completion of the collection, each rat was autopsied todetermine accuracy of probe placement.

[0124] Acetylcholine (ACh) analysis: The concentration of ACh incollected samples of microdialysate was determined usingHPLC/electrochemical detection. Samples were auto-injected (Waters 712Refrigerated Sample Processor) onto a polymeric analytical HPLC column(BAS, MF-6150) and eluted with 50 mM Na₂HPO₄, pH 8.5. To preventbacterial growth, Kathon CG reagent (0.005%) (BAS) was included in themobile phase. Eluent from the analytical column, containing separatedACh and choline, was then immediately passed through an immobilizedenzyme reactor cartridge (BAS, MF-6151) coupled to the column outlet.The reactor contained both acetylcholinesterase and choline oxidasecovalently bound to a polymeric backbone. The action of these enzymes onACh and choline resulted in stoichiometric yields of hydrogen peroxide,which was electrochemically detected using a Waters 460 detectorequipped with a platinum electrode at a working potential of 500 mvolts.Data acquisition was carried out using an IBM Model 70 computer equippedwith a microchannel IEEE board. Integration and quantification of peakswere accomplished using “Maxima” chromatography software (WatersCorporation). Total run time per sample was 11 minutes at a flow rate of1 ml/min. Retention times for acetylcholine and choline were 6.5 and 7.8minutes, respectively. To monitor and correct for possible changes indetector sensitivity during chromatography, ACh standards were includedat the beginning, middle and end of each sample queue.

[0125] Increases in ACh levels are consistent with presynaptic m2receptor antagonism.

RESULTS OF THE TESTS

[0126] For compound numbers 169, 227(−), 289, 269, 214, 232, 123, 236,296, 300, 301, 302, 304, and 305:

[0127] Ki, nM, m1: 2.1 to 224

[0128] Ki, nM, m2: 0.05 to 16.6

[0129] m2 selectivity ration (Ki, m1/Ki, m2)=9.3 to 42

[0130] Ki, nM, m4: 0.33 to 36

[0131] m4 selectivity ration (Ki, m1/Ki, m4): 3 to 12

[0132] For the persently preferred compounds, compound numbers 615, 633,622, 650, 667, 656, 658, 757, 763, 760, 690, 711, 719, 726, 714, 777,795, and 801:

[0133] Ki, nM, m2=0.03 to 0.48

[0134] Selectivity:

[0135] m1/m2=30 to 68

[0136] m3/m2=5 to 66

[0137] m4/m2=2 to 10.

[0138] Presently the most preferred compounds are numbers 667, 760, 801,and 805.

[0139] Numerous other compounds in accordance with formula I were testedwith the following range of results:

[0140] K_(i) binding to m1 receptor, nM: 0.01 to 4770 with undeterminedvalues up to >4200. An undetermined value occurred when a K_(i) was notcompletely determined, but was found to be above some value of up to4200 nM.

[0141] K_(i) binding to m2 receptor, nM: 0.01 to 1525 with undeterminedvalues up to >4600. An undetermined value occurred when a K_(i) was notcompletely determined, but was found to be above some value of up to4600 nM.

[0142] m2 Selectivity Ratio [K_(i) for m1/K_(i) for m2]

[0143] 0.3 to 41.5 without regard to any undetermined K_(i) values.

[0144] When compound No. 169 from the table of compounds wasadministered the following increases in ACh release above baselinelevels were measured. Dosage mg/kg Peak ACh release (Compound 169) as %increase over Baseline From Cortex of Conscious Rat (i.p.administration) (FIG. 1) 30 1500  10 400 1  75 From Striatum ofConscious Rat (i.p. Administration) (FIG. 2) 30 270 10 150 3 125 1  300.1  10

[0145] Oral administration of compound 169 also caused a significantincrease in ACh release.

[0146] We have made the surprising discovery that compounds of formula Iin combination with an acetylcholinesterase (ACh'ase) inhibitor have asynergistic effect on ACh release, as shown below. Here Tacrine was usedas the ACh'ase inhibitor. From Striatum of Conscious Rat Peak AChrelease as % increase over Baseline Dose (FIGS. 3 to 5) Tacrine 3 mg/kg(i.p.)  30 (FIG. 3) Compound 169 1 mg/kg (i.p.)  40 (FIG. 4) Tacrine 3mg/kg and 130 (FIG. 5) Compound 169 1 mg/kg (i.p.)

[0147] As shown immediately above, when administered in combination,compound 169 and tacrine produce a synergistic increase in ACh release.

[0148] The present invention also relates to achieving similarsynergistic results by administering a compound of formula I incombination with any other ACh'ase inhibitor including, but not limitedto, E-2020 (available from Eisai Pharmaceutical) andheptylphysostigmine.

[0149] The present invention also relates to achieving similarsynergistic results by administering any compound capable of enhancingACh release, such as scopolamine or QNB in combination with an ACh'aseinhibitor. Preferably the ACh release enhancing compound is an m2selective muscarinic antagonist, i.e. one having a (K_(i) for m1/K_(i)for m2) ratio greater than 1 or an m4 selective muscarinic antagonist(Ki for m1/Ki for m4 greater than 1). The m2 or m4 selective muscarinicantagonists for practicing this aspect of the invention include withoutlimitation 3-α-chloroimperialine, AF-DX 116, AF-DX 384, BIBN 99 (thesethree compounds being available from Boehringer-Ingleheim),tripitramine, and himbacine.

[0150] For preparing pharmaceutical compositions from the compounds offormula I, compounds capable of enhancing ACh release, and ACh'aseinhibitors, pharmaceutically acceptable, inert carriers are admixed withthe active compounds. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Asolid carrier can be one or more substances which may also act asdilutents, flavoring agents, solubilizers, lubricants, suspendingagents, binders or tablet disintegrating agents; it may also be anencapsulating material.

[0151] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection.

[0152] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parentertal administration. Such liquid forms include solutions,suspensions and emulsions. These particular solid form preparations aremost conveniently provided in unit dose form and as such are used toprovide a single liquid dosage unit.

[0153] The invention also contemplates alternative delivery systemsincluding, but not necessarily limited to, transdermal delivery. Thetransdermal compositions can take the form of creams, lotions and/oremulsions and can be included in a transdermal patch of the matrix orreservoir type as are conventional in the art for this purpose.

[0154] Preferably, the pharmaceutical preparation is in unit dosageform. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active components. The unitdosage form can be a packaged preparation, the package containingdiscrete quantities of preparation such as packeted tablets, capsulesand powders in vials or ampules. The unit dosage form can also be acapsule, cachet or tablet itself, or it may be the appropriate number ofany of these in a packaged form.

[0155] The quantity of active compound in a unit dose preparation may bevaried or adjusted from 1 mg to 100 mg according to the particularapplication and the potency of the active ingredient and the intendedtreatment. This would correspond to a dose of about 0.001 to about 20mg/kg which may be divided over 1 to 3 administrations per day. Thecomposition may, if desired, also contain other therapeutic agents.

[0156] The dosages may be varied depending on the requirement of thepatient, the severity of the condition being treating and the particularcompound being employed. Determination of the proper dosage for aparticular situation is within the skill of those in the medical art.For convenience, the total daily dosage may be divided and administeredin portions throughout the day or by means providing continuousdelivery.

[0157] When a compound of formula I or a compound capable of enhancingACh release is used in combination with an acetylcholinesteraseinhibitor to treat cognitive disorders these two active components maybe co-administered simultaneously or sequentially, or a singlepharmaceutical composition comprising a compound of formula I or acompound capable of enhancing ACh release and an acetylcholinesteraseinhibitor in a pharmaceutically acceptable carrier can be administered.The components of the combination can be administered individually ortogether in any conventional oral or parenteral dosage form such ascapsule, tablet, powder, cachet, suspension, solution, suppository,nasal spray, etc. The dosage of the acetylcholinesterase inhibitor mayrange from 0.001 to 100 mg/kg body weight.

[0158] The invention disclosed herein is exemplified by the followingpreparation and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures may be apparent to those skilled in the art.

PREPARATIONS Preparation 1

[0159]

[0160]21.4 g (130 mmol) of 1 and 15.0 g (108.6 mmol) of 2 were placed ina round bottom flask. DMSO (100 ml) was added and the mixture was warmedto 130° C. where it was stirred for 70 hours. The reaction was cooledand poured into 400 g of ice and stirred thoroughly. The mixture wasfiltered and a white precipitate was collected which was washed withwater. The solid was recrystallized from ethanol.

[0161] Compound 3 (13.72 g, 52.7 mmol) was dissolved in methanol (100ml) and cooled to 0° C. where NaBH₄ (1.29, 31.6 mmol) was added in smallportions. The mixture was stirred for one half hour, then warmed toreflux, stirred for 4 hours, and cooled to room temperature. The solventwas removed on a rotary evaporator. The residue was dissolved in ethylacetate (400 ml) and washed with water and brine, dried over Na₂SO₄ andthen filtered. The solvent was removed with a rotary evaporator.

[0162] A CH₂Cl₂ (120 ml) solution of 4 (14 g, 53 mmol) was cooled to 0°C. and SOCl₂ (7.8 ml, 107 mmol), in 20 ml CH₂Cl₂ was added over a 30minute period. The mixture was warmed to room temperature and stirredovernight. The volatiles were removed on a rotary evaporator and theresidue dissolved in 500 ml ethyl acetate. The organic solution waswashed with water, saturated with NaHCO₃, and brine. The mixture wasdried over Na₂SO₄, filtered and the solvent was removed on a rotaryevaporator.

[0163] Preparation 2

[0164] Compound 6 (25 g, 180 mmol) was dissolved in 80 ml DMF and cooledto 0° C. Sodium hydride (7.2 g 60% dispersion in mineral oil) was addedunder nitrogen. Stirring was continued for 20 minutes then the reactionmixture was warmed to room temperature when compound 5 (20 g, 180 mmol),dissolved in 40 ml DMF, was added with syringe. The solution was heatedto 100° C. and stirred for 3 hours, then cooled to room temperature. DMFwas removed with a rotary evaporator, then 250 ml water was added andthe pH adjusted with NaOH to 12. The solution was extracted with ethylacetate, dried over Na₂SO₄ and filtered. The solvent was then removedwith a rotary evaporator.

[0165] Compound 7 (22 g, 100 mmol) was dissolved in 450 ml EtOH, andcooled to 0° C. NaBH₄ (1.9 g, 51 mmol) was added in portions. Themixture was warmed to room temperature and stirred overnight. Water (300ml) was added and then removed on a rotary evaporator. Ethyl acetate wasadded to the residue which was then washed with water. The organic layerwas dried over Na₂SO₄, filtered, and removed with a rotary evaporator.

[0166] Compound 8 (22 g, 100 mmol) was dissolved in 400 ml CH₂Cl₂ andcooled to 0° C. SOCl₂ (9 ml, 120 mmol) was dissolved in CH₂Cl₂ (50 ml)and added to compound 8 with a dropping funnel, under nitrogen. Afteraddition was complete, the mixture was stirred at 0° C. for ½ an hour,then at room temperature for 2 hours. The solution was decanted into anErlenmeyer flask to remove the precipitate. 10% NaHCO₃ was added untilthe pH of the aqueous layer was 8. The layers were separated and theCH₂Cl₂ layer was dried with MgSO₄. The layer was then filtered and thesolvent was removed on a rotary evaporator.

[0167] Preparation 3

[0168] Compound 10 (54 g, 400 mmol) was dissolved in 500 ml DMF andcooled to 0° C. NaO—CH₃ (20.5 g) was added in portions with stirring.The ice bath was removed and compound 11 (68.4 g, 400 mmol) was addedwith stirring. The mixture stirred at room temperature for 3 hours, thenat 80° C. for 1 hour, and cooled to room temperature. The DMF solutionwas concentrated to 200 ml, then 400 ml water and 300 ml ethyl acetatewas added with stirring by a mechanical stirrer. The pH was made basicwith NaOH, and the organic layer was separated, and dried over MgSO₄.The solution was filtered and the solvent was then removed by a rotaryevaporator.

[0169] Compound 12 (33.4 g, 147 mmol) was dissolved in 1L CH₂Cl₂.Compound 13 (25 g, 148 mmol) and triethylamine (21 ml) were added next.To this solution was added TiCl₄ (75 ml of a 1M CH₂Cl₂ solution).Stirring was continued at room temperature overnight (18 h). Thereaction was quenched with a solution of NaCNBH₃ (27 g, 440 mmol, in 150ml MeOH). After stirring for 2-3 hours, water was added and the pHadjusted to 13 with NaOH. The organic layer was separated and dried overMgSO₄, followed filtration and removal of the solvent. The residue wasdissolved in ethyl acetate and extracted with 3N HCl. The layers wereseparated and the aqueous layer was basified with NaOH (pH=13). CH₂Cl₂was used to extract the aqueous layer. The CH₂Cl₂ layer was then driedover MgSO₄, filtered and evaporated to give compound 14.

[0170] Ethanol (300 ml) was added to compound 14 (17 g, 45 mmol),followed by 2.5 g Pd(OH)₂/C. The mixture was placed on a Parr shaker for1 to 8 hours monitored by TLC at 60 psi of hydrogen then filteredthrough Celite and the EtOH was removed. The residue was dissolved inethyl acetate and washed in NaOH. The pH of the aqueous layer was thenadjusted to 7, then the aqueous layer was extracted with CH₂Cl₂, driedwith Na₂SO₄, then evaporated to produce compound IV′. This was thenrecrystalized from CH₃CN to produce pure IV′.

[0171] Preparation 4

[0172] (Process C)

[0173] 4.3 g (1 equivalent) of 60% sodium hydride dispersion in mineraloil was weighed into a flame-dried 250 ml flask under nitrogen. Themineral oil was removed by washing with hexane, and 100 ml of dryN,N-dimethylformamide was added by syringe. The suspension was cooled inan ice water bath while 15 g (1 equiv.) of 4-methoxythiophenol was addedin portions. The mixture was stirred for 1 hour at room temperatureafter addition was complete, and 14.6 g (12.6 mL, 1.1 equiv.) of4-fluorobenzaldehyde was added in one portion. The mixture was stirredfor 3 days at room temperature, then poured slowly into 600 mL of icewater with vigorous stirring. The yellow solid was separated byfiltration, then triturated twice with 150 mL portions of hexane byvigorous stirring. The product obtained is a light yellow powder, 23 g(88% yield), sufficiently pure for further reaction.

[0174] Preparation 5

[0175] 6.75 grams of bis(paramethoxyphenyl)disulfide were stirred with3.6 mL of glacial acetic acid, and the mixture was cooled to −40° C.Sulfuryl chloride (7.5 mL) was added in portions, and the solution wasmaintained at −40° C. while the solid dissolved. The brown solution waswarmed gradually to −20° C. and stirred for five hours, then warmed to0° C. Gas was evolved during this period, and the solution darkened togreen. The volatiles were removed in vacua, and the crude material wasused in the next reaction without delay.

[0176] Preparation 6

[0177] 6.9 grams (39.1 mm) of (1R,2S)-2-phenylcyclohexanol (prepared inaccordance with J. K. Whitesell, M-S Wong, J. Org. Chem, 56(14), p.4552, 1991) were dissolved in 150 mL dry THF with 6 mL dry pyridine. Thesolution was cooled to −78° C., and para-methoxyphenyl sulfinyl chloride(derived from 6.75 g of the corresponding disulfide) was added slowly.The solution developed a white precipitate as it was stirred at −78° C.for one hour. The reaction was quenched with saturated sodiumbicarbonate, diluted with ethyl acetate, and extracted with bicarbonatesolution and brine. The organic layers were dried over sodium sulfate,concentrated, and purified by column chromatography in a gradient of 10%ethyl acetate/hexane to 25% ethyl acetate/hexane, yielding 10 grams(78%) of the desired sulfinate, slightly contaminated with the minordiastereomer. This diastereomer was purified by crystallization fromhexane/ethyl acetate, a procedure also applicable to the crude product.

[0178] Preparation 7

[0179] 1.25 grams of magnesium turnings (52 mm, 2.3 equivalents) werestirred in 5 mL of dry THF. One drop of 1,2-dibromoethane was added,followed by a small portion (roughly one gram) of 4-bromobenzaldehydediethyl acetal. The solution was heated to initiate formation of theGrignard reagent, and the remaining acetal (to a total of 11.2 grams, 45mm, 2 equivalents) was added in portions, along with THF (to a total of25 mL.) The mixture was heated to reflux for 45 minutes, then cooled toroom temperature. The Grignard solution thus obtained was added inportions to a solution of the starting sulfinate ester (7.5 grams, 22.6mm) in 150 mL dry toluene at 0° C. After one hour, the reaction wasquenched with saturated sodium bicarbonate solution, diluted with ethylacetate, and extracted with brine. The organic layers were dried oversodium sulfate, concentrated, and purified by brief column chomatographyin 25% ethyl acetate/hexane to give recovered chiral alcohol and thedesired acetal, which was used directly in the next reaction.

[0180] Preparation 8

[0181] The acetal obtained from the reaction of 7.5 grams of sulfinateester was taken up in 60 mL of THF with 10 mL distilled water. Acatalytic amount of paratoluene sulfonic acid was added, and thesolution was warmed to 60°. After three hours, the mixture was cooled toroom temperature, diluted with ethyl acetate, and extracted withsaturated sodium bicarbonate solution. The organic layers were driedover sodium sulfate and concentrated to give the desired aldehyde as acrystalline solid, 5.42 grams (97% over two steps).

[0182] Preparation 9

[0183] 2 grams (8.17 mm) of the starting4-(4-methoxyphenyl)thiobenzaldeyde and 1.75 g (1 equivalent of 80%)meta-chloroperbenzoic acid were taken up in 40 mL of dichloromethane at0°. After 30 minutes, 300 mg of additional MCPBA was added, and thereaction stirred 30 minutes more. The solution was diluted with ethylacetate and extracted with saturated sodium bicarbonate. The organiclayers were dried over sodium sulfate, concentrated, and the product wascrystallized from ethyl acetate/hexane to give a first crop of 1.65grams.

EXAMPLE 1

[0184] (Process A)

[0185] Compound II′ (1.0 g, 3.5 mmol) was dissovled in DMF (10 ml),followed by addition of K₂CO₃ (1.5 g). Compound III′ (0.66 g, 3.9 mmol)was next added. The mixture was warmed to 50° C. and maintained for 18hours with stirring. The mixture was cooled to room temperature andethyl acetate (EtOAc) (150 ml) was added. The organic layer was washedwith water (5×50 ml) and saturated NaCl (1×25 ml). The organic layer wasdried over Na₂SO₄, filtered, and the volatiles removed with a rotaryevaporator. The resulting oil was purified by column chromatography, onsilica gel, with ethyl acetate as solvent.

EXAMPLE 2

[0186] (Process A)

[0187] To the solid chloride (770 mg) was added a solution of 2equivalents of cyclohexylpiperazine in 5 mL CH₃CN. The mixture washeated with stirring at reflux for 2 hours then allowed to stand for 18hours. The resulting solid was suspended in 1:1 EtOAc: water. Theaqueous layer was basified with solid K₂CO₃. The organic layer waswashed several times with water, dried with MgSO₄ and evaporated toobtain the crude product. This was purified by chromatography on acolumn of silica gel, (TLC grade), and 50:3:1 CH₂Cl₂:EtOH:NH₄OH as theeluant.

EXAMPLE 3

[0188] (Process B)

[0189] To an ice cold solution of compound IV′ (1 equivalent) in dry DMFunder nitrogen was added 0.9 equivalents of NaH, (60% dispersion inmineral oil). After 20 minutes 2-chloropyrimidine was added (0.9equivalents). The solution was heated at 100° C. for 4 hours. Aftercooling to room temperature water was added (10 mls per 1 ml DMF) andthe solution extracted with ethyl acetate. The organic extracts weredried with MgSO₄ and evaporated to obtain the crude product which wasthen purified by column chromatography, (Silica gel, TLC grade and50:3:1 CH₂Cl₂:EtOH:NH₄OH as eluant).

EXAMPLE 4

[0190] (Process C)

[0191] To a solution of VI′ (0.25 g, 0.73 mmol) in 5 ml acetonitrile wasadded a solution of VII′ (0.12 g, 0.73 mmol, dissolved in 3 mlacetonitrile). The mixture was stirred at room temperature (20° C.) for0.5 hours, then warmed to 45° C. and stirred for 6 hours. The mixturewas cooled to room temperature and ethyl acetate (150 ml) was added andthe organic layer was washed with saturated NaCl (1×50 ml). The organiclayer was dried over Na₂SO₄. The organic layer was filtered and thevolatiles removed with a rotary evaporator. The resulting oil waspurified by flash chromatography using 50 g silica gel and 9:1CH₂Cl₂/MeOH (saturated with NH₄OH) as solvent. 0.19 g of a syrup wascollected.

EXAMPLE 5 (Process D)

[0192]

[0193] 2 grams (8.17 mmol) of the starting4-(4-methoxyphenyl)thiobenzaldehyde, VIII′, and 1.65 g (10 ml, 1.2equivalents) of N-cyclohexylpiperazine, X′, were taken up under anitrogen atmosphere in 1 mL of dry dichloromethane at room temperature.2.9 mL (10 mmol, 1.2 equivalents) of titanium tetraisopropoxide wereadded by syringe, and the resulting solution was stirred at roomtemperature for 18 hours. The reaction developed a white precipitateduring this period. The reaction was cooled in an ice water bath while16.3 mL of a 1 molar toluene solution (2 equivalents) of diethylaluminumcyanide were added in portions by syringe. The resulting homogeneousred/brown solution was stirred for 30 minutes at room temperature. Thereaction was diluted by the addition of 100 mL ethyl acetate, andquenched by the slow addition of 25 mL water, with vigorous stirring.After 1 hour, the inorganic solids were removed by filtration throughCelite, and the filtrate was washed with a saturated brine solution anddried by anhydrous sodium sulfate. The product was concentrated, thenpurified by column chromatography in a gradient of acetate/hexane,yielding 3.29 grams of the desired product (95% yield.)

EXAMPLE 6

[0194] Hydrolysis of cyano compound to amide

[0195] 2 grams (4.6 mm) of the starting nitrile were stirred in 25 mL oftertiary butanol with 1.2 grams (21 mm) of powdered potassium hydroxide.The mixture was heated to reflux for 30 minutes, cooled to roomtemperature, and diluted with 250 mL of water. The solution wasextracted twice with ethyl acetate, and the organic layers were driedover sodium sulfate. Evaporation gave the amide (2 grams, 96%) as anamorphous solid which can be used in subsequent reactions withoutfurther purification.

EXAMPLE 7

[0196] Hydrolysis of amide to acid

[0197] 0.95 grams of starting amide (2.1 mm) were taken up in 20 mL of4N hydrochloric acid. The reaction was heated to reflux for 16 hours.The volume of the solution was reduced in vacuo, whereupon thedihydrochloride salt of the desired product precipitated. The solid wasisolated by filtration and washed with dry ethyl ether to give 0.85grams of product, 77% yield. This solid was suitable for use withoutfurther purification.

EXAMPLE 8

[0198] Formation of Methyl Ester

[0199] A solution of methanolic HCl was prepared by the addition of 3 mLof acetyl chloride to 50 mL of dry methanol. To this solution was added400 milligrams (0.88 mm) of the starting acid. The flask was fitted witha Soxhlet extraction thimble containing freshly activated molecularsieves (3 Å), and the solution was heated to reflux for 16 hours. Thereaction was cooled to room temperature, and the acid was neutralizedwith solid sodium carbonate. The solution was diluted with 300 mL ofdichloromethane and washed with distilled water. The organic layers weredried over magnesium sulfate and purified by column chromotography in 3%methanol/dichloromethane to give 310 milligrams (76%) of the desiredproduct.

EXAMPLE 9

[0200] Formation of tetrazole

[0201] 250 milligrams (0.57 mm) of the starting nitrile were taken upunder a nitrogen atmosphere in 4 mL of dry toluene with 0.15 mLtrimethylsilyl azide (2 equivalents) and 14 milligrams of dibutyltinoxide (1 equivalent). The solution was heated at 100° for 48 hours,whereupon additional equivalents of the azide and tin reagents wereadded and the solution was heated an additional 24 hours. The reactionwas cooled to room temperature and evaporated to a brown solid, whichwas purified by preparative thin-layer chromatography in 20%methanol/dichloromethane. 27 milligrams of the desired tetrazole wereisolated.

EXAMPLE 10

[0202] Alkylation of tetrazole

[0203] 20 milligrams (0.57 mm) of the starting tetrazole were treatedwith an ethereal solution of diazomethane (excess) at 0°. The solutionbecame homogeneous after ten minutes, and after an additional thirtyminutes the solution was evaporated and purified by preparativethin-layer chromatograpy in 7.5% methanol/dichloromethane. 10 milligramsof product were isolated.

EXAMPLE 11

[0204] (Process E)

[0205] Alkylation of methyl ester

[0206] 100 milligrams (0.2 mm) of the starting ester were taken up undera nitrogen atmosphere in 4 mL of dry tetrahydrofuran at 0°. 0.53 mL(0.26 mm, 1.3 equivalents) of potassium hexamethyidisilazide solution(0.5 M in toluene) were added by syringe, and the resulting solution wasstirred for ten minutes. 0.02 mL of iodomethane (1.3 equivalents) werethen added by syringe The reaction was stirred for 20 minutes whilewarming to room temperature, then diluted by the addition of 50 mL ethylacetate, and extracted with saturated sodium bicarbonate solution andbrine. The organic layers were dried by anhydrous sodium sulfate,concentrated, and purified by preparative thin-layer chromotagraphy in5% methanol/dichloromethane, giving 24 milligrams of the desiredproduct.

EXAMPLE 12

[0207] Alpha-alkylation of cyano compounds

[0208] 200 milligrams (0.46 mm) of the starting nitrile were taken upunder a nitrogen atmosphere in 10 mL of dry tetrahydrofuran at 0°. 1.2mL (0.6 mm, 1.3 equivalents) of potassium hexamethyidisilazide solution(0.5 M in toluene) were added by syringe, and the resulting orangesolution was stirred for ten minutes. 0.05 mL of iodomethane (1.3equivalents) were added by syringe, which decolorized the solution. Thereaction was stirred for 20 minutes while warming to room temperature,then diluted by the addition of 100 mL ethyl acetate, and extracted withsaturated sodium bicarbonate solution and brine. The organic layers weredried by anhydrous sodium sulfate, concentrated, and purified by columnchromatography in a gradient of hexane/ethyl acetate, giving 190milligrams of the desired product (92% yield) as an oil that slowlysolidified.

EXAMPLE 13

[0209] Oxidation of Sulfide to Sulfoxide

[0210] 1.82 grams of the starting sulfide (4.4 mm) were dissolved in 20mL of dichloromethane and 17 mL of a 0.5 N solution of methanesulfonicacid in dichloromethane. 1.15 grams of commercial MCPBA (60-80% pure)were added at 0°, and the solution was stirred for thirty minutes. Thereaction mixture was diluted with ethyl acetate and extracted withsaturated sodium bicarbonate. The organic layers were dried over sodiumsulfate, concentrated, and purified by column chromatography in agradient of 75% ethyl acetate/hexane to 5% methanol/ethyl acetate togive 1.22 grams of the desired sulfoxide and 0.4 grams of thecorresponding sulfone.

EXAMPLE 14

[0211] Synthesis of compounds 300, 301, 302, 304, and 760.

[0212] Step 1:

[0213] To a stirred mixture of 501 (5.0 g) in 50 ml of aqueous NaOH (20%w/w) was added, at 0° C., Di-tert-butyloxy dicarbonate (3.4 g, 1.2 eq.)dissovled in 50 ml of diethyl ether. The cooling bath was removed andthe mixture was stirred at room temperature for 2 hours. Two phases wereseparated and the aqueous phase was extracted with 2×50 ml of ethylacetate. The combined organic phases were dried over Na₂SO₄, filteredand concentrated to give a crude product. Purification by flashchromatography on silica gel (10% EtOAc-Hex.) afforded 3.5 g (89%) of502 as a white solid (m.p.=89-90° C.).

[0214] Step 2:

[0215] NaH (460 mg, 60% in mineral oil) was washed with dry hexanes andwas stirred with 8 ml of dry DMF. To this mixtue was added4-methoxythiophenol by syringe. The mixture was stirred at RT for 20min. while the slurry became a clear solution. Compound 502 dissolved in8 ml of DMF was added dropwise and the mixture was stirred at roomtemperature over night. Water (80 ml) was added and the mixture wasextracted with 3×100 ml of EtOAc. The combined organic phases were driedover Na₂SO₄, filtered and concentrated to give a crude. Purification byflash chromatography on silica gel (20% EtOAc-Hex.) afforded 3.6 g (74%)of 503 as a white solid (m.p.=105-107° C.).

[0216] Step 3:

[0217] To a solution of 503 (1.5 g) in 40 ml of dry THF at 0° C., wasadded MeMgBr (1.15 ml, 3.0 M in ether). The mixture was stirred at 0° C.for 1 h. and was quenched with 20 ml of a 10% KHSO₄. The aqueous phasewas extracted with 2×50 ml of ethyl acetate. The combined organic phaseswere dried over Na₂SO₄, filtered and concentrated to give a crude.Purification by flash chromatography on silica gel (30% EtOAc-Hex.)afforded 1.3 g (96%) of 504 as a solid, mp 129-130°.

[0218] Step 4:

[0219] At 0° C., 1.3 g of 504 was dissolved in a mixture of 5 ml TFA and15 ml CH₂Cl₂. The cooling bath was removed and the mixture was stirredat RT for 2 h, quenched with saturated bicarbonate at 0° C., and theaqueous layer extracted with EtOAc. The combined organic phases weredried over Na₂SO₄, filtered and concentrated to give a white solidcompound 505 which was used in the next step without furtherpurification.

[0220] Step 5:

[0221] The white solid from step 4 was dissolved in 10 ml methylenechloride and to this solution was added 350 mg of cyclohexanone followedby 1.3 g of titanium (IV) isopropoxide. The mixture was stirred at RTover night. At 0° C., 440 mg of NaCNBH₃, dissolved in 2 ml of methanolwas added and the mixture was stirred at RT for an additional 3 h. Themixture was quenched with water and extracted with EtOAc. The combinedorganic phases were dried over Na₂SO₄, filtered and concentrated to givea crude product. Purification by flash chromatography on silica gel(100% EtOAc) afforded 0.5 g (40%) of Compound 302 as a white solid. Thesolid was dissolved in ethyl acetate, and treated with 2-3 equivalentsof ethereal dry HCl. The mixture was evaporated to dryness in vacuo togive the hydrochloride, m.p. 227-30°.

[0222] Step 6:

[0223] To a stirred solution of 350 mg of compound 302 in 60 ml EtOAcand 60 ml CH₂Cl₂ were added 1.7 ml of MeSO₃H (0.5 M in CH₂Cl₂), followedby 262 mg of mCPBA (50-60%) at −40° C. The mixture was allowed to reach0° C. and was quenched with saturated bicarbonate solution (100 ml). Themixture was extracted with 3×100 ml of EtOAc. The combined organicphases were dried over Na₂SO₄, filtered and concentrated to give a crudeproduct. Purification by flash chromatography on silica gel (15%EtOH-EtOAc) afforded 0.2 g (55%) of compound 304 as a white solid.

[0224] HPLC Separation of compound 304 on a Chiralcel OJ column; (ChiralTechnologies, Inc., Exton, Pa.):

[0225] Compound 304 was separated on a 100-200 mg scale under thefollowing conditions:

[0226] Solvent system: 0.1% diethyl amine/3% ethanol/hexane

[0227] Flow rate: 160 ml/min

[0228] Retention Time: 70 min for enantiomer A (compound 300,mp=141-142)

[0229] 90 min for enantiomer B (compound 301, mp=141)

[0230] Synthesis of Compound 760:

[0231] Compound 505 (0.375 g, 1.15 mmol) and4-carboethoxycyclohexanonone (0.294 g, 1.72 mmol) were dissolved in 6 mLof CH₂Cl₂. The reaction mixture was then cooled to 0° C. followed byaddition of Ti(i-PrO)₄ (1.3 mL, 4.42 mmol). The reaction mixture wasstirred at room temperature overnight, when TLC indicated there was nostarting material. To the reaction mixture was slowly added a solutionof NaCNBH₃ (0.364 g, 5.8 mmol) in MeOH (2 mL). The reaction mixture wasthen stirred at room temperature for 2 h. The reaction was quenched byaddition of 50 mL of 1N NaOH followed by 50 mL of ethyl acetate. Thereaction mixture was stirred at room temperature for 1 h then wasextracted with ethyl acetate (50 mL×3). The organic layer was dried withNaHCO₃. Solvent was removed and the residue was separated on a silicagel column (5% methanol/CH₂Cl₂) to afford the sulfide (0.46 g, 83%yield) as an oil.

[0232] The sulfide (0.038 g, 0.08 mmol) was dissolved in 2 mL of HOAcfollowed by addition of NaBO₃/4H₂O (0.037 g, 0.24 mmol). The reactionmixture was stirred at room temperature overnight, when TLC indicatedthere was no starting material. To the reaction mixture was then added1N NaOH until basic. The reaction mixture was extracted with ethylacetate (20 mL×3). The organic layer was dried with NaHCO₃. Solvent wasremoved and the residue was separated on a silica gel column (5%methanol/CH₂Cl₂) to afford Sch 65546 (0.007 mg, 17% yield) as an oil.

EXAMPLE 15

[0233] Synthesis of Compound 306.

[0234] Preparation of 511

[0235] To a solution of 25 mmol of cyclohexanone in 20 ml of acetic acidis added 62.5 mmol of cyclohexylpiperazine. The system is blanketed withN₂ and 31.3 mmol of TMS-cyanide, is added. The solution is then heatedat 60° C. under N₂ for approximately 20 hours. Acetic acid is removed ona rotary evaporator and the residue treated with 100 ml of water. Thisis extracted with EtOAc, (3×, 50 ml). Organic layers are washed with 100ml. of water, dried with Na₂SO₄ and evaporated to give the crude productas an oil which is purified by column chromatograpy using 100:3:1CH₂Cl₂:EtOH:NH₄OH as eluant. An oil was obtained, 10 g of which wasdissolved in 100 ml CH₂Cl₂ and 50 ml water, then basified to pH 8 withK₂CO₃. The organic layer was dried with Na₂SO₄ and evaporated to obtaina light yellow powder, 6.6 g.

[0236] Preparation of Compound 306:

[0237] In a three necked round bottomed flask is placed 5.4 mmol of Mgand the flask is fitted with a condenser, dropping funnel and nitrogeninlet. The system is flame dried under nitrogen. Bromodiphenyylether(5.4 mmol), is dissolved in anhydrous THF, (10 ml), and added dropwise.Addition of a drop of ethylene dibromide, iodine and occasional warmingmay be necessary to initiate Grignard formation. Once initiated themixture is heated at reflux until all the Mg dissolves. Next, 1.8 mmolof cyanoamine 511 as a solution in 5 ml of dry THF is added, reflux iscontinued, and the reaction monitored by TLC.

[0238] The reaction mixture is cooled to room temperature and quenchedby addition of a saturated NH₄Cl solution, (10 ml ). This is dilutedwith 10 ml of water and extracted with 15 ml EtOAc. (3×). The organicextracts are dried with Na₂SO₄ and evaporated to give the crude productas an oil which is purified by column chromatography using ether/EtOAcas eluant. 370 ml of clear colorless oil was obtained.

[0239] The dimaleate salt was prepared by dissolving the oil in 10 ml ofEtOAc and treating with 200 mg of maleic acid. A white powder wasobtained (510 mg, mp=144-146).

EXAMPLE 16

[0240] Synthesis of Compound 303

[0241] Example 15 is repeated except in place of cyclohexanone there isused a compound of the formula

[0242] Compound 303 is obtained as a di-maleate:

EXAMPLE 17

[0243]

[0244] NaH (334 mg, 60% oil suspension) was washed with 15 ml of hexane,then stirred with 5 ml of DMF. Compound 522 (1.03 ml) was added withoutsolvent, the mixture stirred at room temperature for 20 min, a solutionof 521 (2.42 g obtained by reductive alkylation) in 1.7 ml of hot DMFadded, and the resulting mixture stirred at room temperature for twodays. The mixture was quenched with water, and extracted with ethylacetate. The extracts were purified by flash chromoatography over SiO₂to give 3.0 g of product 523, mp 128-9°.

[0245] m-Chloroperbenzoic acid (MCPBA, 81 mg) was added to a solution of523 (105 mg) and MeSO₃H (0.5 M in CH₂Cl₂, 1.0 ml) in 50 ml of ethylacetate at −40°. Sufficient CH₂Cl₂ was added at this temperature toeffect dissolution of solids, and the mixture allowed to warm to roomtemperature. The mixture was quenched with excess NaHCO₃ solution, andextracted with ethyl acetate. The extracts were concentrated andpurified by preparative thin-layer chromatography, developing with 20%ethanol-ethyl acetate to give Compound 305 N-oxide. This material wasdissolved in CH₂Cl₂, CS₂ added, and the resulting mixture stirred for 3hrs. at room temperature. Evaporation of volatiles and purification ofthe residue by preparative TLC as above gave Compound 305, mp 125°.

EXAMPLE 18 (Process F)

[0246] Preparation of compounds 3-10 shown in Process F, where R is4-methoxyohenyl, R3 and R4 are H, R1 is (S)—CH₃, and R27 is (R)—CH₃ andPreparation of Compound (3)

[0247] To an ice cooled solution of trifluoroacetic anhydride (19 mL) inCH₂Cl₂ (100 mL) add over 15 min (S)-(−)-α-methylbenzylamine (12.2 g) inCH₂Cl₂ (25 mL) with stirring, then stir at RT for 1 h. Cool in ice andadd methanesulfonic acid (40 mL) then powdered dibromodimethyl hydantoin(15 g). Stir till dissolved, then store for 20 h at RT, protected fromlight. Add to a stirred solution of NaHSO₃ (5 g) in ice-H₂O (100 mL),stir 5 min., separate, extract with CH₂Cl₂, wash the combined organicswith H₂O and dry (MgSO₄). Filter on 30 g flash silica and elute withCH₂Cl₂ (300 mL). Evaporate the total eluates to dryness, add Et₂O (100mL), stir 10 min. and add hexanes (500 mL). Stir 0.5 h, filter, washwith hexanes and dry to obtain the 4-bromocompound (12.3 g) as whitecrystals.

[0248] Mp: 153-155°. Mass spectrum: MH+=296/298.

[0249] Preparation of Compound (4)

[0250] Cool a solution of compound (3) (11.95 g) in dry THF (160 mL) to−70° under N₂ and add methyllithium (1.4M in Et₂O, 28.8 mL). Stir 5 min.then add n-butyllithium (2.5M in hexanes, 17 mL). Stir 5 min. then add4-methoxybenzenesulfonyl fluoride (16 g). remove the cooling bath, stirfor 0.5 h, add 1N-HCl aq. (200 mL) and exteract with CH₂Cl₂. Wash withH₂O, dry (MgSO₄) and filter on a 15 g pad of flash silica gel, wash with5% Et₂O—CH₂Cl₂ and evaporate. Recrystallise with Et₂O-hexanes and dry togive the sulfone (13.4 g) as off-white crystals.

[0251] Mp: 97-100°. Mass spectrum: MH+=388.

[0252] Preparation of Compound (5)

[0253] Reflux on a steam bath for 2 h a mixture of compound (4) (17.5 g)and NaOH (6 g) in H₂O (15 mL) and ethanol (120 mL). Cool, add H₂O andextract with CH₂Cl₂. Dry over K₂CO₃, filter and evaporate. Trituratewith Et₂O-hexanes till solid, filter and dry to afford the amine (10.4g), as a white solid.

[0254] Mp: 113-115°. Mass spectrum: MH+=292

[0255] Preparation of Compound (6)

[0256] To solution of compound (5) (1.46 g) in CH₂Cl₂ (20 mL) andpotassium carbonate (2 g) in H₂O (10 mL) add ethyl (S)-lactatetrifluoromethanesulfonate (1.1 g) and stir at RT for 5 h. Wash withwater, dry (MgSO₄), evaporate and chromatograph on flash silica gel,eluting with a 0-15% gradient of Et₂O in CH₂Cl₂. Evaporate the purefractions and triturate in hexanes to obtain the crystalline ester (1.90g)

[0257] Mp: 56-58°. Mass spectrum: MH+=392.

[0258] Preparation of Compound (7)

[0259] Reflux a mixture of compound (6) (1.73 g), acetonitrile (15 mL),anhydrous sodium carbonate (1.5 g) and ethyl iodoacetate (1.4 mL) for 48h., work up in H₂O—CH₂Cl₂, dry (MgSO₄) and evaporate. Chromatograph onsilica, using a 0 to 10% gradient of Et₂O in CH₂Cl₂ and evaporateappropriate pure fractions to separately obtain the solid product (1.46g) and recovered starting aminoester (0.53 g).

[0260] Mp: 69-71°. Mass spectrum: MH+=478.

[0261] Preparation of Compound (8)

[0262] Stir lithium aluminum hydride (0.45 g) in THF (15 mL) under N₂with ice cooling and add over 2-3 min. a solution of diester (7) (1.30g) in THF (25 mL). Stir in ice for 0.5 h., add EtOAc (5 mL) dropwise,then add the solution to stirred, ice cooled 2N-NaOH solution (50 mL).Separate, extract the aq. with 3:1 Et₂O—CH₂Cl₂, combine, dry andevaporate the organics and triturate with a little Et₂O to obtain thediol as a white powder (0.88 g).

[0263] Mp: 123-125°. Mass spectrum: MH+=394.

[0264] Preparation of mixture (10)

[0265] Reflux a mixture of compound (8) (0.125 g), thionyl chloride(0.25 mL) and 1,2-dichloroethane (5 mL) for 1.5 h., evaporate,co-evaporate with 3 mL dichloroethane and dry at high vacuum to obtainthe mixture of dichlorocompounds as a pale yellow foam, suitable for usein the next step.

[0266] Preparation of compound numbers 730 and 803

[0267] These compounds are examples of compounds 11 and 12 as shown forprocess f.

[0268] Convert diol (0.125 g) to the dichlorides as described above,then reflux this product for 2 h. in acetonitrile (2.5 mL) withtrans-4-aminocyclohexanol hydrochloride (0.32 g), sodium iodide (0.5 g)and diisopropylethylamine (0.6 mL). Cool, and partition in H₂O—CH₂Cl₂.Dry and evaporate the organic phase, and subject the residue topreparative TLC, eluting with acetone. Extract the separated bands with1:1 CH₂Cl₂—MeOH, evaporate and dry at high vacuum to obtain the freebases as foams.

[0269] The less polar band (0.056 g) is compound no. 730. Dissolve thisin CH₂Cl₂ (2 mL) and add to stirred Et₂O (15 mL) containing 4MHCl-dioxan (0.4 mL). Centrifuge, wash by suspension-centrifugation inether (2×15 mL) and dry under N₂ to obtain the dihydrochloride as awhite powder.

[0270] Mp: 195-205°, with decomposition. Mass spectrum: MH+=473.

[0271] The more polar band (0.076 g) is compound 803. Convert this tothe hydrochloride as above.

[0272] Mp: 215-225 C, with decomposition. Mass Spectrum MH+=473

EXAMPLE 19 (Process G)

[0273] Preparation of compound 667 and 656

[0274] Step 1 (a)

[0275] A solution of the aldehyde (Compound VII′ of preparation 4,Process C, 4.9 g, 0.02 mol) in 50 mL THF was cooled in an ice water bathand methylmagnesium bromide (8.5 mL, 3.0M) was slowly added. After 0.5 hthe temperature was warmed to room temperature where stirring wascontinued for 16 h. After dilution with ethyl acetate and addition ofwater the organic layer was washed with water, brine, and concentrated.Drying under vacuum produced a yellow oil (5.1 g) which was used withoutfurther purification.

[0276] A dichloromethane (150 mL) solution of the sulfide was cooled inan ice water bath where MCPBA (11.7 g, 60%) was added. After stirringfor 1 h the temperature was warmed to room temperature and stirred for16 h. After diluting with ethyl acetate the reaction was washed with 10%sodium carbonate, water, and brine. The solution was concentrated andpurified by chromatography with ethyl acetate to the sulfone alcohol.

[0277] Step 1(b)

[0278] To a clear pale yellow solution of the p-anisylthioacetophenone 1(0.8 g; 3.1 mmol) in anhydrous tetrahydrofuran (5 mL) was added(S)-oxaborolidine catalyst 2 (0.168 g; 0.6 mmol) and stirred at roomtemperature for 15 minutes. A solution of borane-methyl sulfide intetrahydrofuran (2M from Aldrich Chemicals; 1.86 mmol; 0.93 mL) wasadded dropwise over 6 minutes to the solution of ketone 1 and catalyst 2at room temperature. After 10 minutes of stirring, thin layerchromatography (TLC) showed absence of starting material and formationof a new, slightly more polar spot. The reaction was quenched by addingmethanol (5 mL) and stirring for 15 minutes. Volatiles were removed onthe rotary evaporator and the residue was dissolved in methylenechloride (50 mL). The organic extract was washed with water, 1N.HCl,water, 10% NaHCO₃, brine and dried over magnesium sulfate. Concentrationof the organic extract gave the carbinol 3 as a clear pale yellow oil(0.76 g; yield=94%).

[0279] HPLC: AS-Column (5% i-PrOH in Hexanes); R_(t)˜19 min; R: S=97:3(94% ee/R-Alcohol)

[α]D=+26.1 (c=0.1; CHCl₃)

[0280] A clear pale yellow solution of 3 (0.76 g; 2.92 mmol) inanhydrous dichloroethane (8 mL) at room temperature was treatedsequentially with solid NaHCO₃ (0.6 g; 7 mmol) and solidmeta-chloroperoxybenzoic acid (1.1 g; 6.43 mmol). The flask was fittedwith a reflux condenser and the reaction mixture was heated to reflux.TLC at the end of 8 hours showed absence of 3 and formation of a morepolar spot. Reaction mixture was allowed to cool to room teperature. Theorganic layer was decanted away from the white precipitate of sodiumsalts, washing the solid residue with methylene chloride (2×20 mL). Thecombined organic extract was washed with water, 10% Na₂S₂O₃ solution,water, 10% NaHCO₃ solution and brine. Dried the organic layer overmagnesium sulfate and concentrated to obtain −0.8 g of a pale yellowsolid. Flash silicagel chromatography (20% EtOAc-CH₂Cl₂) gave 0.75 g(88% from 1) of sulfone as a white solid, mp: 125-126° C. [α]D=+22.1(C=0.095; CHCl₃)

[0281] Step 2:

[0282] To a suspension of the alcohol (4.0 g, 13.6 mmol) indichloromethane (30 mL) was added triethylamine (2.75 g, 27.2 mmol). Themixture was cooled in an ice/water bath and methanesulfonyl chloride(1.87 g, 16.3 mmol) was added dropwise. After 1 h the mixture wasdiluted with dichloromethane and washed with water, 2% HCl, water, 10%NaHCO₃ and brine. After drying over sodium sulfate the solvent wasevaporated to afford the crude product as a gum. It was used withoutfurther purification.

[0283] Step 3:

[0284] 2-(R)-Methylpiperazine (30 g, 0.3 mol) and cyclohexanone (32 g,0.33 mol) were dissolved in methylene chloride (60 mL) and cooled in anice/water bath where titanium (IV) isopropoxide (93 g, 0.33 mol) wasadded dropwise. Stirring was continued for 1 h at 0° C. then at roomtemperature for 16 h. A solution of sodium cyanoborohydride (21 g, 0.33mol) in methanol (200 mL) was added with stirring continued for 24 h.The mixture was diluted with 1L ethyl acetate and stirred with 400 mL10% NaOH for 1 h. The aqueous solution containing a white precipitatewas discarded. The organic layer was washed with water and brine,followed by concentration on a rotary evaporator. The residue purifiedby flash chromatography with 25:1 CH₂Cl₂/MeOH (saturated with aqueousammonia), yield=50%.

[0285] The mesylate from step 2 (4.8 g, 13 mmol) and1-cyclohexyl-3(R)-methylpiperazine (3.5 g, 19.4 mmol) were dissolved in40 mL CH₃CN and heated to 60 C where stirring was continued for 24 h,then refluxed for 8 h. The solvent was removed and the residue dissolvedin ethyl acetate. The organic layer was washed with 10% sodium carbonateand brine. The solvent was evaporated and the residue chromatographedwith 4:1 dichloromethanelacetone. When step 1a is used, twodiastereomers (compounds 656 and 667) were collected in a 1:1 ratio(656: R_(f)0.40, ethyl acetate: Anal. cale. C, 68.39; H, 7.95;, N, 6.13;S, 7.02; found C, 68.01; H, 8.02; N, 6.09; S, 7.05. 667: R_(f)0.30,ethyl acetate: found C, 68.06; H, 8.08; N, 6.18; S, 6.84). When step 1bis used starting with the (S)-oxaborolidine shown, then the product is656 while (R)-oxaborolidine catalyst gives 667.

[0286] By appropriate choice of starting materials, the followingcompounds were prepared. In these tables the following notes apply.

[0287] t-BOC means t-butloxycarbonyl. The compound numbering is notconsecutive. A (+) or (−) after a compound number indicates the opticalrotation of the stereoisomer for which data is given. “IsoA” or “IsoB”after a compound number indicates an assignment of A or B to differentstereoisomers of a compound having the same structural formulas withoutregard to optical rotation. When the chiral atom has been identified,“isoA” or “isoB” is listed after a substituent for that atom. NBA isnitrobenzyl alcohol, G/TG is glycerol/thioglycerol. Chex meanscyclohexyl. Compounds having the formula

# R X R¹ R² Mass Spectrum or MP  1 C₆H₅ S CH₃ CH₃ MP = 254-256 (di-HCl) 2 C₆H₅ SO₂ CH₃ CH₃ MP = 226-230 (di-HCl)  3 C₆H₅ SO CH₃ CH₃ MP =240-242 (di-HCl)  4 C₆H₅ SO CH₃ H MP = 80-85 (dimaleate)  5 C₆H₅ S CH₃ HMP = 227-229 (di-HCl)  6 C₆H₅ SO₂ CH₃ H MP = 180-220 di-HCl hydrate  7C₆H₅ SO₂ CH₃ (CH₂)₂OH MP = 236-238 (di-HCl)  8 4-Cl—C₆H₄ SO₂ CH₃(CH₂)₂OH MP = 242-244 (di-HCl)  9 C₆H₅ O CH₃ (CH₂)₂OH Cl(CH₄):327(M +1), 309, 197  10 (+) C₆H₅ SO₂ CH₃ (CH₂)₂OH FAB -NBA-G/TG-DMSO:375(M + 1)  11 (−) C₆H₅ SO₂ CH₃ (CH₂)₂OH FAB-NBA-G/TG-DMSO:375(M + 1)  122-pyridyl O CH₃ CH₃ MP = 172-175 (Dimaleate)  13 C₆H₅ O CH₃(CH₂)₂O(CH₂)₂OH El:370 (M+), 197,99  14 C₆H₅ SO₂ i-Pr (CH₂)₂OH El:(M +1)402, 359, 329, 128,  15 C₆H₅ SO₂ CH₃ 2-CH₃O—C₆H₄ FAB-NBA-G/TG-DMSO:437M + 1)  16 C₆H₅ SO₂ CH₃ cyclohexyl Cl(CH₄):(m + 1) 413  17 C₆H₅ SO₂ i-Prcyclohexyl Cl(CH₄:(M +‘1) 441, 397, 299  18 4-CH₃C₆H₄ SO₂ CH₃ cyclohexylEl:427(M + 1), 383, 167  19 C₆H₅ SO₂ CH₃ C₆H₅ SIMS-NBA-G/TG-DMSO:407(M + 1), 232  20 3-pyridyl O CH₃ (CH₂)₂OH MP = 165-168 (Dimaleate)  213-pyridyl O CH₃ cyclohexyl MP = 219-222 Dimaleate  22 3-pyridyl S CH₃(CH₂)₂OH MP = 155-158 Dimaleate  23 3-pyridyl S CH₃ cyclohexyl MP =159-159 (Dimaleate)  24 2-CH₃-4-pyridyl O CH₃ (CH₂)₂OH MP = 165-166(Dimaleate)  25 2-CH₃-4-pyridyl O CH₃ cyclohexyl MP =90-91  26 C₆H₅ OCH₃ cyclohexyl El:364 (M+), 349, 197, 167  27 C₆H₅ SO₂ C₆H₅ cyclohexylFAB-NBA-G/TG-DMSO:(M + 1) 475, 335, 307, 257  28 C₆H₅ SO₂ i-Pr (CH₂)₃OHFAB-G/TG-DMSO:(M + 1) 417, 373, 315, 273  29 C₆H₅ SO₂ i-Pr(CH₂)₂O(CH₂)₂OH FAB-NBA-G/TG-DMSO:(M + 1) 447, 404, 329, 315  30 C₆H₅SO₂ n-Bu cyclohexyl MP = 217-220  31 4-Cl—C₆H₄ SO₂ i-Pr cyclohexyl MP =134-137 (dec)  32 4-CH₃—C₆H₄ SO₂ i-Pr cyclohexyl MP = 208-210  33 C₆H₅SO₂ CH₃ 4-NO₂—C₆H₄ FAB-NBA-G/TG-DMSO:452(M + 1  34 C₆H₅ SO₂ CH₃ (CH₂)₃OHFAB-NBA-G/TG-DMSO:389(M + 1)  35 4-CH₃—C₆H₄ SO₂ CH₃ 2,3-(CH₃)₂-C₆H₃Cl(CH₄):449(M + 1), 191, 148  36 4-Cl—C₆H₄ SO₂ CH₃ cyclohexylFAB-NBA-G/TG-DMSO:447 M + 1)  37 3-pyridyl O i-Pr cyclohexyl MP =150-153 (Difumarate)  38 4(CH₃O)C₆H₄ SO₂ i-Pr cyclohexyl Cl(CH₄):(M +1)471, 427, 305, 289, 144,  39 4-Cl—C₆H₄ SO₂ C₆H₅ cyclohexylFAB-NBA-G/TG-DMSO:510 (M + 1), 399, 341  40 4-Cl—C₆H₄ SO₂ n-Bucyclohexyl FAB-NBA-G/TG-DMSO: 489 (M + 1), 349, 314  41 4-(t-Bu)C₆H₄ SO₂i-Pr cyclohexyl FAB-NBA-G/TG-DMSO:497 (M + 1), 453, 371, 329, 301, 223 42 3-Cl—C₆H₄ SO₂ CH₃ cyclohexyl Cl(CH₄):447 (M + 1)  43 C₆H₅ SO₂cyclohexyl cyclohexyl Cl(CH₄):481 (M + 1), 341, 315, 219, 169, 167, 111,79  44 C₆H₅ SO₂ CN cyclohexyl Cl(CH₄):424 (M + 1), 397, 328, 286, 258,233, 197, 169, 167, 111, 79  45 C₆H₅ O CH₃ (CH₂)₂-O-t-BOCFAB-SIMS-NBA-G/TG-DMSO:411 (M + 1), 308, 197  46 (+) 4-CH₃—C₆H₄ SO₂ CH₃cyclohexyl El:427 (m + 1), 388, 167  47(−) 4-CH₃—C₆H₄ SO₂ CH₃ cyclohexylEl:427 (m + 1), 388, 167  48 C₆H₅ O CH₃ (CH₂)₂-O-t-BOC Cl(Isobutane):425(M + 1)  49 4-t-Bu-C₆H₄ SO₂ CH₃ cyclohexyl Cl(CH₄):(M + 1) 469, 456  504(CH₃O)C₆H₄ SO₂ CH₃ cyclohexyl Cl(CH₄):(M + 1) 443, 399, 167, 125  514-CH₃—C₆H₄ SO₂ CN cyclohexyl Cl(Isobutane):438(M + 1), 411, 272, 261,169  52 2,4-(Cl)₂—C₆H₃ O CH₃ cyclohexyl Cl(Isobutane):435(M + 2), 434,433, 314, 312, 267, 265, 195, 169, 167  53 4-CH₃—C₆H₄ SO₂ CH₃(CH₂)₂NHCOCH₃ Cl(CH₄):430 (M + 1), 357  54 4-t-Bu-C₆H₄ O CH₃ cyclohexylCl(Isobutane):421 (M + 1) 349. 335, 261, 259, 91  55 n-Bu O CH₃cyclohexyl Cl(Isobutane):345 (M + 1), 177, 169  56 4-CH₃—C₆H₄ SO₂ CH₃CH₂CONH₂ Cl(CH₄):402 (M + 1)  57 2-pyrimidyl O CH₃ cyclohexyl MP =191-193 (Dimaleate)  58 4-CH₃-3-pyridyl O CH₃ cyclohexyl MP = 168-170(Dimaleate)  59 4-CH₃—C₆H₄ SO₂ CH₃ CH₂-cyclohexyl Cl(CH₄):441 (M + 1) 60 3-pyridyl O CH₃ CH₂-cyclohexyl MP = 187-189 (Dimateate)  612-benzoxazolyl O CH₃ cyclohexyl MP = 165-168 (Maleate)  62 3-pyridyl OCH₃ CH₂CH(OH)C₆H₅ MP = 162-164 Dimaleate  63 3-pyridyl O CH₃bicyclo[2.2.1]hept-2-yl MP = 168-175 (Dimaleate)  64 C₆H₅ O CH₃(CH₂)₂OCOCH₂-tBU Cl(CH₄):425 (M + 1), 309, 197  65 1-Me-2-imidazolyl SCH₃ cyclohexyl MP = 155-158 (Dimaleate)  66 2-pyrimidyl O CH₃cyclopentyl MP = 178-181 (Dimaleate)  67 2-pyrimidyl O CH₃ cycloheptylMP = 167-171 (Dimaleate)  68 2-pyrimidyl O CH₃ tetrahydrothiapyran-4-ylMP = 157-160 (Dimaleate)  69 2-pyrimidyl O CH₃ 3-Me-2-butenyl MP =180-182 (Dimaleate)  70 2-pyrimidyl O CH₃ 2-cyclohexenyl MP = 171-174(Dimaleate)  71 2,4-(MeO)2-6- O CH₃ cyclohexyl MP = 196-199 (Dimaleate)pyrimidyl  72 4-CF₃-2-pyridyl O CH₃ cyclohexyl MP = 178-182 Dimaleate 73 3-Me-2-butenyl O CH₃ cyclohexyl MP = 194-197 Dimaleate)  742-pyrimidyl S CH₃ cyclohexyl MP = 182-184 (Dimaleate)  754-Me-2-pyrimidyl S CH₃ cyclohexyl MP = 163-165 (Dimaleate)  76 3-pyridylO CH₃ 1-azabicyclo[2.2.2]-oct-3-yl MP = 182-184  77 3,4-(MeO)₂-C₆H₃ SO₂CH₃ cyclohexyl SIMS-NBA-G/TG-DMSO:473 (M + 1), 399, 337 305, 273, 214 78 4-Me-2-pyrimidyl O CH₃ cyclohexyl MP = 179-181 (Dimaleate)  794-HO—C₆H₄ O CH₃ cyclohexyl Cl(CH₄):(M + 1) 381, 287, 241, 213, 195, 167, 80 4-Et-C₆H₄ O CH₃ cyclohexyl Cl(CH₄):(M + 1)393, 377, 253, 225, 195,169,  81 1-piperidyl CH₂ CH₃ cyclohexyl Cl(Isobutane):(M + 1) 370,  834-CH₃-C₆H₄ SO₂ CH₃ 2-ketocyclohexyl Cl(CH₄):441(M + 1), 345, 261  844-CH₃—C₆H₄ SO₂ CH₃ (CH₂)₂OH SIMS-NBA-G/TG-DMSO:389 (M + 1)  853,5-(CH₃)₂-C₆H₃ O CH₃ cyclohexyl El:(M + 1) 392, 377, 343, 327, 225,155,  86 4-CH₃O—C₆H₄ O CH₃ cyclohexyl Cl(Isobutane):395 (M + 1), 269,227, 181, 169  87 2-cyclohexenyl O CH₃ cyclohexyl Cl(Isobutane):369 (M +1), 288  88 4-Cl-2-pyrimidyl O CH₃ cyclohexyl MP = 160-161 (Dimaleate) 89 4,6-(Cl₂-2- O CH₃ cyclohexyl MP = 180-182.5 (Dimaleate) pyrimidyl 90 2,4-(MeO)₂-1,3,5- O CH₃ cyclohexyl MP = 198-200 (Dimaleate)triazin-6-yl  91(−) 2-pyrimidyl O CH₃ cyclohexyl Cl(CH₄):367 (M + 1),199, 142  92(+) 3-Cl—C₆H₄ SO₂ CH₃ cyctohexyl Cl(CH₄): 449, 447 (M + 1), 93(−) 3-Cl—C₆H₄ SO₂ CH₃ cyclohexyl Cl(CH₄):449, 447 (M + 1),  94 (+)2-pyrimidyl O CH₃ cyclohexyl Cl(CH₄):367 (M + 1), 199, 142  95tetrahydropyran-4-yl O CH₃ cyclohexyl MP = 218-220 (diHCl)  962,3,5-(Me)₃-C₆H₂ O CH₃ cyclohexyl El(M + 1):406, 266, 239, 167  974-CH₃—C₆H₄ SO₂ CH₃ 1-methytbutyl SIMS-NBA-G/TG-DMSO:415(M + 1)  98 C₆H₅S CH₃ cyclohexyl Cl(CH₄):381(M + 1)  99 6-Cl-3-pyridazinyl O CH₃cyclohexyl MP = 115-117 100 6-MeO-3- O CH₃ cyclohexyl MP = 123-127pyridazinyl 101 3-pyridazinyl O CH₃ cyclohexyl MP = 113-115 102 2-MeS-4-O CH₃ cyclohexyl MP = 185-187 (Dimaleate) pyrimidinyl 103 2-thiazolyl OCH₃ cyclohexyl MP = 184-186 (Dimaleate) 104 pivaloyl O CH₃ cyclohexylCl(CH₄):373 (M + 1), 205, 169, 167, 121 106 4-CH₃O—C₆H₄ S CH₃ cyclohexylCl(Isobutane:(M + 1) 411, 243, 169, 107 3,4-(MeO)₂C₆H₃ S CH₃ cyclohexylCl(CH₄):(M + 1) 441, 273, 164, 108 C₆H₅ C(CH₃) CH₃ cyclohexyl MP =185-18 Dimaleate (OH) 109 N-morpholinyl CH₂ CH₃ cyclohexyl Cl(CH₄):372(M + 1), 285, 249, 204, 191, 169, 167, 119 110 4-Me-piperazin-1-yl CH₂CH₃ cyclohexyl Cl(CH₄):385(M + 1), 217, 195, 169, 113, 89 111 C₆H₅ C═CH₂CH₃ cyclohexyl MP = 189-191 (Dimaleate) 112 C₆H₅ CHOH CH₃ cyclohexylCl(CH₄):379 (M + 1), 362, 301, 273, 211, 195, 169, 166 113 pyrazinyl OCH₃ cyctohexyl MP = 110-111 114 2-propynyl O CH₃ cyclohexyl MP = 173-175(Dimaleate) 115 2-hydroxyethyl O CH₃ cyclohexyl Cl(CH₄):(M + 1) 333,317, 205, 165, 121 116 benzyl O CH₃ cyclohexyl El:(M + 1) 470, 455, 330,303, 167 117 H CO CH₃ cyclohexyl Cl(CH₄):301 (M + 1), 385, 195, 169,135, 118 CH₃ CO CH₃ cyclohexyl MP = 158-161 (dimaleate) 119 4-CH₃O—C₆H₄CHOH CH₃ cyclohexyl El:408, 279, 268, 241, 167, 135, 126. 120 (Me)₂NCO OCH₃ cyclohexyl Cl(CH₄):(M + 1) 360, 273, 220, 192, 108 121 4-NO₂—C₆H₄ OCH₃ cyctohexyl SIMS-NBA-G/TG-DMSO:409 (M + 1), 393, 366, 338, 283, 270,242, 196, 167 122 4-HO—C₆H₄ S CH₃ cyclohexyl Cl(CH₄):(M + 1) 397, 257,229, 195, 167 123 4-CH₃O—C₆H₄ SO CH₃ cyclohexyl SIMS-NBA-G/TG-DMSO:427.2(M + 1), 343 124 C₆H₅ CH═CH CH₃ cyclohexyl MP = 108-111 125 4-CH₃O—C₆H₄CO CH₃ cyclohexyl Cl(CH₄):407 (M + 1), 299, 269, 241, 197, 169, 167,135. 126 3-CH₃O—C₆H₄ S CH₃ cyclohexyl Cl(CH₄):411, (M + 1), 271, 245,243, 195, 169, 166. 127 4-Br-2,3,5,6- O CH₃ cyclohexyl Cl(CH₄):515 (M +1), 437, 435, 271, 269, tetrafluoro-phenyl 191, 167. 128 3-CH₃O—C₆H₄ SOCH₃ cyclohexyl MP = 231-234 129 4-CHO—C₆H₅ O CH₃ cyclohexylSIMS-NBA-G/TG-DMSO:393 (M + 1), 365, 307, 289, 273, 262, 257, 246, 225130 4-HO—C₆H₅ SO CH₃ cyclohexyl Cl(CH₄):(M+ 1) 413, 397, 271, 229, 167131 3,4-(CH₃O)₂C₆H₄ SO CH₃ cyclohexyl Cl(Isobutane):(M + 1) 457, 441,132 3-phenyl-2- O CH₃ cyclohexyl MP = 191-194 (Dimaleate) propynyl 1333-phenyl-2- O CH₃ cyclohexyl MP = 145-148 (HCl) propenyl 134 2-butynyl OCH₃ cyclohexyl MP = 190-192 (dimaleate) 135 4-CH₃O—C₆H₄ SO₂ CNcyclohexyl SIMS-NBA-G/TG DMSO 454:(M + 1), 427, 399, 346, 299, 274, 257,238, 215 136 2-pyrimidinyl SO₂ CH₃ cyclohexyl MP = 194-195 (dimaleate)137 2-pyrimidinyl SO CH₃ cyclohexyl MP = 165-167 (dimaleate) 1383-pyridyl SO CH₃ cyclohexyl MP = 123-125 139 3-pyridyl SO₂ CH₃cyclohexyl MP = 142-145 140 3-CH₃O—C₆H₄ O CH₃ cyclohexylSIMS-NBA-G/TG-DMSO:395.4 (M + 1), 142 4-CH₃O—C₆H₄ C═NOH CH₃ cyclohexylEl:(M + 1) 421, 405, 378, 265, 239, ISO 1 143 4-CH₃O—C₆H₄ C═NOH CH₃cyclohexyl El:(M + 1) 421, 405, 377, 265, 254 ISO 2 144 4-CH₃O—C₆H₄ S CNcyclohexyl SIMS-NBA-G/TG-DMSO:422 (M + 1), 395, 300, 273, 257, 254, 238145 4-CH₃O—C₆H₄ SO CN cyclohexyl Cl(CH₄):438.2(M + 1), 411.3, 331, 254.2146 benzyl C≡C CH₃ cyclohexyl MP = 180-183 (dimaleate) 1471-Me-1-propynyl O CH₃ cyclohexyl MP = 174-176 (dimaleate) 1484-CH₃O—C₆H₄ C═NOCH₃ CH₃ cyclohexyl Cl(Isobutane):(M + 1) 436, 404, 1502-(CH₃O)C₆H₄ CHOH CH₃ cyclohexyl El:(M + 1) 408, 393, 282, 241, 167 1512-thienyl C(CH₃) CH₃ cyclohexyl MP = 147-149 (OH) 152 4(CF₃O)C₆H₄ SO₂CH₃ cyclohexyl SIMS-NBA-G/TG-DMSO:497 (M + 1), 481, 413, 329, 257, 238153 2(CH₃O)C₆H₄ CO CH₃ cyclohexyl FAB(+ve)-HMR:(M + 1) 407, 397, 329,307, 260, 237, 154 CH₃COOC₆H₄ S CH₃ cyclohexyl El:(M + 1) 438, 395, 298,271, 229, 167, 155 4-CH₃SO₂—C₆H₄ SO₂ CH₃ cyclohexyl FAB(+ve)-HMR:(M + 1)491, 475, 391, 365, 273, 257 156 C₆H₅ SO iso A CH₃ cyclohexylCl(CH₄):397 (M + 1), 382, 213, 167 158 C₆H₅ SO iso B CH₃ cyclohexylCl(CH₄):397 (M + 1), 382, 213, 167 159 2-pentynyl O CH₃ cyclohexyl191-193 (dimaleate) 160 2-thienyl C═CH₂ CH₃ cyclohexyl MP = 173-176(dimaleate) 161 C₆H₅ O CH₃ (CH₂)₂OCOC(Me)₂ Cl(CH₄):439(M + 1) n-C₃C₇ 1623-butenoyl NH CH₃ cyclohexyl MP = 155-156 163 4(CH₃O)C₆H₄ CH₂ CH₃cyclohexyl Cl(Isobutane):393 (M + 1), 379, 285, 225, 169 164 3-(3,4- NHCH₃ cyclohexyl SIMS-NBA-G/TG-DMSO:462 (M + 1), 294, methylenedioxy- 174,169, 120 phenyl)-2- propenoyl 165 trifluoroacetyl NH CH₃ cyclohexyl MP =127-130 166 CH₃ C═N—O-2- CH₃ cyclohexyl MP = 173-174 (dimaleate)pyrimidyl 167 4(CH₃S)C₆H₄ S CH₃ cyclohexyl Cl(CH₄(M + 1) 427, 303, 259,195, 167, 168 4(CH₃)C₆H₄ SO₂ CH₃ (CH₂)₃N(Et)COC(Me)₂ Cl(CH₄):514 (M + 1)n-C₃H₇ 169 4(CH₃O)C₆H₄ SO CN cyclohexyl SIMS-NBA-G/TG-DMSO:438 (M + 1),411, IsoA 395, 331, 254, 246, 214 170 4-CH₃SO₂—C₆H₄ SO CH₃ cyclohexylCl(Isobutane):(M + 1)475, 459 171 4-CH₃SO—C₆H₄ SO CH₃ cyclohexylFAB(+ve)-HMR:(M + 1) 458, 443, 365, 307, 273, 257 172 p-toluenesulfonylNH CH₃ cyclohexyl El:441, 301, 273, 167, 118 173 methanesulfonyl NH CH₃cyclohexyl Cl(CH₄):399 (M + 1), 260, 169 174 2-propynyl NH CH₃cyclohexyl Cl(CH₄):326 (M + 1), 195, 158 175 2-pyrimidinyl S CNcyclohexyl Cl(CH₄):394 (M + 1), 367, 257, 217, 167. 1764-Me-1-piperazinyl SO₂ CH₃ cyclohexyl Cl(CH₄):435 (M + 1), 269, 217,183, 170, 167. 177 4(CH₃O)C₆H₄ SO CN cyclohexylSIMS-NBA-G/TG-DMSO:438(M + 1), 411, IsoB IsoB 395, 331, 254, 246, 214178 C₆H₄ SO CN cyclohexyl Cl(Isobutane):(M + 1) 408, 381, 233, 169 ISO B179 2-pyrimidinyl SO CN cyclohexyl SIMS-NBA-G/TG-DMSO) 410 (M + 1), 383,331, 307 180 1-piperidyl SO₂ CH₃ cyclohexyl Cl(Isobutane):420 (M + 1),376, 188, 167, 140, 125, 112, 85 181 N-morpholino SO₂ CH₃ cyclohexylCl(Isobutane):372, (m + 1) 370, 285, 249, 204, 191, 170, 167, 119, 100,88 182 2-thiazolyl S CH₃ cyclohexyl 179-180 dimaleate 183 2-thiazolyl SOCH₃ cyclohexyl MP = 179-180 (dimaleate) 184 6-Cl-3-pyridazinyl S CH₃cyclohexyl MP = 123-125 185 6-Cl-3-pyridazinyl SO₂ CH₃ cyclohexyl MP =154-156 186 6-Cl-3-pyridazinyl SO CH₃ cyclohexyl MP = 135-137 1874-(CH₃SO)C₆H₄ S CH₃ cyclohexyl FAB(+ve)-HMR:(M + 1) 433, 427, 275, 259,169, 188 t-BOCNH/9C/h₂)₇CO NH CH₃ cyclohexyl SIMS-NBA-G/TG-DMSO:529 (M +1), 261 189 4(CH₃O)C₆H₄ S CH₂NH₂ cyclohexyl Cl(Isobutane):(M + 1) 426,395, 190 propadienyl S CH₃ cyclohexyl MP = 175-177 (dimaleate) 191propadienyl SO₂ CH₃ cyclohexyl MP = 143-145 (dimaleate) 192 propadienylSO CH₃ cyclohexyl MP = 159-161 (dimateate) 193 2-propynyl SO CH₃cyclohexyl MP = 153-156 (dimaleate) 194 1-propynyl S CH₃ cyclohexyl MP =180-183 (dimaleate) 195 2-pyrimidinyl O C₆H₅ cyclohexylSIMS-NBA-G/TG-DMSO:429 (M + 1), 308, 261 196 propadienyl O CH₃cyclohexyl MP = 149-152 (dimaleate) 197 4(CH₃O)C₆H₄ SO CN Isomer Bcyclohexyl SIMS-NBA-G/TG-DMSO:438 (M + 1), 411, Isomer A 395, 331, 254,246, 214 198 4(CH₃O)C₆H₄ SO CH₃ cyclohexyl SIMS-NBA-G/TG-DMSO:427 (M +1), 343 Isomer A 200 4(CH₃O)C₆H₄ SO iso B CN iso A cyclohexylSIMS-NBA-G/TG-DMSO:438 (M + 1), 411, 395, 331, 254, 246, 214 201 C₆H₅ OH cyclohexyl Cl(CH₄):351 (M + 1) 202 C₆H₅ O CN cyclohexylSIMS-NBA-G/TG-DMSO:375 (M + 1) 203 6-(MeNH)- SO₂ CH₃ cyclohexyl MP =177-179 3-pyridazinyl 204 6-(MeNH)- SO CH₃ cyclohexyl MP = 113-135 2052-propynyl S CH₃ cyclohexyl 170-173 (dimaleate) 207 4-(CH₃O)C₆H₄ S Hcyclohexyl Cl(Isobutane):(M + 1) 397, 208 2-propynyt NMe CH₃ cyclohexylMP = 73-76 209 2-propynyl O CN cyclohexyl MP = 125-130 (maleate) 2106-(MeO)-3- SO₂ CH₃ cyclohexyl MP = 165-167 (dimaleate) pyridazinyl 2114(CH₃O)C₆H₄ SO iso A CN iso A) cyclohexyl SIMS-NBA-G/TG-DMSO:438 (M +1), 411, 395, 331, 254, 246, 214 212 2-pyrimidinyl O cyclohexylcyclohexyl Cl(Isobutane):435 (M + 1), 351 213 2-pyrimidinyl O CNcyclohexyl FAB-NBA-G/TG-DMSO:378 (M + 1), 351 214 4(CH₃O)C₆H₄ SO₂ CO₂CH₃cyclohexyl FAB-NBA-G/TG-DMSO:(m + 1)487, 455, 429, 391, 232 215 C₆H₅ OCN cyclohexyl Cl(CH₄):376 (M + 1), 349 216 4-HO—C₆H₄ SO CN cyclohexylSIMS-G/TG-DMSO-30% TFA:(M + 1) 424, 408, 397, 381 217 4-(CH₃O)C₆H₄ SO₂cyclohexyl cyclohexyl El: 510, 427 218 4-(CH₃O)C₆H₄ SO cyclohexylcyclohexyl El: 494, 411 219 4-(CH₃O)C₆H₄ S cyclohexyl cyclohexyl El:478, 395, 328, 245, 229 220 4-(CH₃O)C₆H₄ SO₂ CONH₂ cyclohexylSIMS-NBA-G/TG-DMSO (M + 1) 472, 456, 427, 345, 232 221 4-(CH₃O)C₆H₄ SOC(NH₂)═NOH cyclohexyl FAB-NBA-G/TG-DMSO:(m + 1)471, 411, 391, 293, 257,232, 222 4-(CH₃O)C₆H₄ SO CONH₂ cyclohexyl FAB-NBA-G/TG-DMSO:456 (M + 1),411, 349, 272 223 1-propynyl S CN cyclohexyl MP = 173-175 maleate 2244-(CH₃O)C₆H₄ SO CO₂CH₃ cyclohexyl FAB-NBA-G/TG-DMSO:471 (M + 1), 455,411, 364, 287, 273 225 cyclopropylmethyl O CH₃ cyclohexyl MP = 197-198(dimaleate) 226 2-propynyl S CN cyclohexyl 123-125 (maleate) 227(−)2-pyrimidinyl O cyclohexyl cyclohexyl Cl(CH₄):435 (M + 1), 267 2282-pyrimidinyl O cyclohexyl cyclohexyl Cl(CH₄):435 (M + 1), 267 (+) 2291-propynyl S cyclohexyl cyclohexyl MP = 159-162 (dimaleate) 2302-butynyl O CN cyclohexyl MP = 137-140 (maleate) 231 2-pyrimidinyl O1-Me-4- cyclohexyl El:449, 351, 282, 185. piperidynyl 232 2-pyriminyl Oi-Pr cyclohexyl SIMS-NBA-G/TG-DMSO:395 (M + 1), 227 233 4(CH₃O)C₆H₄ SCO₂CH₃ cyclohexyl SIMS-NBA-G/TG-DMSO:455 (M + 1), 395, 287, 246 2344(CH₃O)C₆H₄ SO 5-tetrazolyl cyclohexyl SIMS-NBA-G/TG-DMSO:(M + 1), 481465, 456, 411, 395 235 2-pyrimidinyl O cyclopentyl cyclohexyl M.P. =165-8 (HCl) 236 4(CH₃O)C₆H₄ SO 2-Me-5- cyclohexyl FAB-NBA-G/TG-DMSO:495(M + 1), 471, tetrazolyl 438, 411, 283, 273, 246, 232 237 4(CH₃O)C₆H₄ Sallyl cyclohexyl FAB-NBA-G/TG-DMSO:437 (M + 1), 395, 313, 264, 246, 242238 2-propynyl O CN cyclohexyl M.P.= 115-117 239 2-propynyl O CH₃cyclohexyl M.P. = 178-180 (Dimaleate) 240 4(CH₃O)C₆H₄ SO 3-TMS-4-cyctohexyl FAB-NBA-G/TG-DMSO: 552 (M + 1), 536, (1,2,3)-tri- 368, 356,214 azolyl 241 2-pyrimidinyl O allyl cyclohexyl M.P. = 225-7 (HCL) 1994-(CH₃)—C₆H₄ SO CON(Me)2 cyclohexyl FAB-NBA-G/TG-DMSO:468 (M + 1), 431,395, 304, 300 Compounds having, the formula

242 C₆H SO₂ CH₃ CH₃ El:343(M), 125 243 2-pyrimidinyl O CN chexSIMS-NBA-G/TG-DMSO:377 (M + 1) 141 C₆H₅ O H chex FAB-NBA-G/TG-DMSO: 350(M + 1) 149 3-Cl—C₆H₅ SO₂ ═CH₂ CH₃ FAB-NBA-G/TG-DMSO:376 (M + 1)Compounds having the formula

244 C₆H₅ SO₂ i-Pr N(CH₃)₂ FAB-NBA-G/TG-DMSO:(M + 1) 401, 356, 312, 273245 C₆H₅ SO₂ 1-piperidyl Cl(CH₄):(M + 1) 475, 307 246 4-CH₃—C₆H₄ SO₂i-Pr 1-piperidyl 247 2-pyrimidinyl O CH₃ CH₃ Cl(CH₄):298 (M + 1), 282,199, 126. Cl(City) 248 4-CH₃—C₆H₄ SO₂ CH₃ CH₃ El:358 (M + 1), 342 2494-CH₃—C₆H₄ SO₂ CH₃ CO₂Et SIMS-NBA-G/TG-DMSO:416 (M + 1) 250 4-CH₃—C₆H₄SO₂ CH₃ benzyl SIMS-NBA-G/TG-DMSO:434 (M + 1) 251 2-pyrimidinyl O CH₃1-piperidyl Cl(CH₄):367 (M + 1) 281, 199, 167 252 2-pyrimidinyl O CH₃chex SIMS-NBA-G/TG-DMSO:366 (M + 1), 350 253 C₆H₅ SO₂ H (CH₂)₃N(Et)COCSIMS-NBA-G/TG-DMSO:513 (M + 1) (Me)₂ n-C₃H₇ 254 C₆H₅ SO₂ CH₃ CH₃Cl(CH₄):344 (M + 1) 255 C₆H₅ SO₂ CH₃ chex Cl(CH₄):412 (M + 1) 256 C₆H₅ OCH₃ CH₃ Cl(CH₄):296 (M + 1) 82 4-CH₃—C₆H₆ SO₂ CH₃ chex Cl(CH₄):426(M + 1) 342, 270, 166 Compounds having the formula

# R X R¹ R² Mass Spectrum or MP 257 C₆H₅ SO₂ H chex SIMS-G/TG-DMSO:413(M + 1) 258 C₆H₅ SO₂ H chex Isomer A SIMS-NBA-G/TG-DMSO:413 (M + 1) 259C₆H₅ SO₂ H chex Isomer B Cl(CH₄):413 (M + 1) 260 3-Cl—C₆H₄ SO₂ H chexIsomer B SIMS-NBA-G/TG-DMSO:463, 461 (M + 1) 261 2-pyramidinyl O CH₃chex Isomer A Cl(CH₄):381 (M + 1), 199. 262 2-pyramidinyl O CH₃ chexIsomer B SIMS-NBA-G/TG-DMSO:381 (M + 1) 263 4(CH₃O)C₆H₄ SO CN chexIsomer A SIMS-NBA-G/TG-DMSO:452 (M + 1) iso A 206 4-CH₃O—C₆H₄ SO CN chexIsomer B Cl(Isobutane):452 (M + 1), 425 IsoB SO Compounds having theformula

# R X R¹ R² Mass Spectrum or MP= 265 C₆H₅ SO₂ H chex El:412, 369, 181,126. 266 C₆H₅ SO₂ H chex Isomer A SIMS-NBA-G/TG-DMSO:413 (M + 1) 267C₆H₅ SO₂ H chex Isomer B Cl(CH₄):413 (M + 1) 268 C₆H₅ SO₂ SO₂ chexCl(CH₄):427 (M + 1) 269 2-pyrimidinyl O SO₂ chex SIMS-NBA-G/TG-DMSO:381(M + 1), 199 270 2-pyrimidinyl O 1-Me-4- chex Cl(CH₄):464 (M + 1), 462,282 piperidinyl 271 2-pyrimidinyl O i-Pr chex SIMS-NBA-G/TG-DMSO:409(M + 1), 227 272 2-pyrimidinyl O H chex Cl(CH₄):367 (M + 1) 2732-pyrimidinyl O n-hexyl chex SIMS-NBA-G/TG-DMSO:451 (M + 1), 269 2742-pyrimidinyl O chex chex Cl(CH₄):449 (M + 1), 365, 267 Iso.A 2752-pyrimidinyl O chex chex Cl(CH₄):449 (M + 1), 365, 267 Iso.B 157 C₆H₅SO₂ H 2- SIMS-NBA-G/TG-DMSO:411 (M + 1) cyclohex enyl Compounds havingthe formula

# Mass Spectrum or MP 280 R is 4-CH₃—C₆H₄: X is SO_(2:) R¹ is CH₃;R^(2 is)

R³, R⁴, R⁸, R⁹, and R²¹ are H; Y and Z are N mass spec Cl(CH₄):429(M + 1) 281 R is 4-CH₃—C₆H₄; X is SO₂; R¹ is CH₃; R² is chex; R³ isOCH₃; R⁴, R⁸, R⁹, and R²¹ are H; and Y and Z are N mass spec Cl(CH₄):457(M + 1) 282 R is 4-CH₃—C₆H₄; X is SO₂; R¹ is CH₃; R² is chex; R³ is H;R⁴ is F; R⁸, R⁹, and R²¹ are H; Y and Z are N mass spec Cl(CH₄):(M + 1)445, 289, 277, 195, 167 283 R is C₆H₅; X is SO₂; R¹ is CH₃; R² is chex;R³ is Cl; R⁴, R⁸, R⁹, and R²¹ are H; Y and Z are N; mass specCl(CH₄):449, 447, (M + 1) 284 R is 4-CH₃—C₆H₄; X is SO₂; R¹ is CH₃; R²,R³ and R⁴ are H; R⁹ is CH₂OH, R⁴ and R²¹ are H; Y is N; Z is CH₂; massspectrum Cl(CH₄);374 (M + 1), 261. 285 R is 4-(CH₃O)C₆H₄; X is

R¹ is CH₃; R² is chex; R³, R⁴, R⁸, R⁹, and R²¹ are H, Y and Z are N massspectrum El: (M + 1) 482, 467, 439, 343, 255, 211, 167 286 R is CH₃; Xis

R¹ is CH₃; R² is chex; R³, R⁴, R⁸, R⁹ and R²¹ are H; Y and Z are N MP =173-175 dimaleate 287 R is C₆H₅; X is SO₂; R¹ is H, R² is chex; R³ isCl; R⁴ and R⁵ are H; R⁹ is (R)—CH₃, R²¹ is H; Y and Z are N; mass specCl(CH₄):447 (M + 1) 288 R is 4-(CH₃O)—C₆H₄; X is SO; R¹ is CN; R² ischex; R³, R⁴, R⁸, and R⁹ are H; R²¹ is CH₂CO₂CH₃; Y and Z are N; massspec SIMS-NBA-G/TG-DMSO) 510.2 (M + 1) 483.2, 307.1, 273.1, 246.1, 214289 R is 4-(CH₃O)—C₆H₄; X is SO; R¹ is CN; R² is chex; R³, R⁴, R⁸, andR⁹ are H; R²¹ is CH₃; Y and Z are N mass spec SIMS-NBA-G/TG-DMSO:452.2(M + 1), 425.2, 293.1, 268.1, 257.1 290 R is 4(CH₃O)C₆H₄; X is SO; R¹ isCN; R² is chex; R³, R⁴, R⁸, and R⁹ are H; R²¹ is CO₂Me; Y and Z are Nmass spec FAB-NBA-G/TG-DMSO: 496 (M + 1), 480, 469, 454, 389, 312 291 Ris 2-pyrimidinyl; X is O; R¹ is CH₃; R² is chex; R³ and R⁴ are H; R⁸ is(S)—CH₃; R⁹ and R²¹ are H; Y and Z are N; mass specFAB-NBA-G/TG-DMSO:381 (M + 1), 199. 292 R is 2-pyrimidinyl; X is O; R¹is H; R² is chex; R³ and R⁴ are H; R⁸ is (S)—CH₃; R⁹ and R²¹ are H; Yand Z are N; mass spec FAB-NBA-G/TG-DMSO: 267 (M +1) 293 R is2-pyrimidinyl; X is O; R¹ is H; R² is chex; R³ and R⁴ are H; R⁸ is(R)—CH₃; R⁹ and R²¹ are H; Y and Z are N; mass specFAB-NBA-G/TG-DMSO:367(M + 1) 294 R is 2-pyrimidinyl; X is 0; R¹ is CH₃;R² is chex; R³ and R⁴ are H; R⁸ is (R)—CH₃; R⁹ and R²¹ are H; Y and Zare N; M.P. = 170-173 (HCL) 295 R is 4-(CH₃O)—C₆H₄; X is SO; R¹ is CN;R² is chex; R³, R⁴, R⁸ and R⁹ are H; R²¹ is CN; Y and Z are N; mass specFAB-NBA-G/TG-DMSO:463 (M + 1), 436, 356, 307, 273 296 R is 4(CH₃O)—C₆H₄;X is SO; R¹ is CH₃; R² is chex; R³, R⁴, R⁸, and R⁹ are H; R²¹ is CO₂Me;Y and Z are N; mass spec FAB-NBA-G/TG-DMSO:485 (M + 1), 471, 425, 381,365, 338, 320 297 R is 2-propynyl; X is 0; R¹ is CH₃; R² is chex; R⁴ isCl; R³, R⁸, R⁹, and R²¹ are H; Y and Z are N M.P. = 172-174 (dimaleate)298 R is 4-(CH₃O)—C₆H₄; X is SO; R¹ is CN; R² is chex; R³, R⁴, R⁸ and R⁹are H; R²¹ is allyl; Y and Z are N; mass spec FAB-NBA-G/TG-DMSO:478 (M +1), 451, 354, 294, 246 299 R is 2-propynyl; X is O; R¹ is CN; R² ischex; R⁴ is Cl; R³, R⁸, R⁹ are H; Y and Z are N M.P. = 132-134 (maleate)300 R is 4(CH₃O)—C₆H₄; X is SO; R¹ and R²¹ togehter form ═CH₂; R² iscyclobexxyl, y is CH, Z is N, R³, R⁴, R⁸ and R⁹ are H - sulfoxide isomerA 301 n is 4(CH₃O)—C₆H₄; X is SO; R¹ and R²¹ togehter form ═CH₂; R² iscyclohexxyl, y is CH, Z i N, R³, R⁴, R⁸ and R⁹ are H - sulfoxide isomerB; mp = 141-142 302 R is 4(CH₃O)—C₆H₄; X is 5; R¹ and R²¹ together form═CH₂; R² is cyclohexyl, Y is CH, Z is N, R³, R⁴, R⁸ and R⁹ are H; mp =227-230 (HCl) 303 R^(1 is C) ₆H₅; X is O; R¹ and R²¹ together form

Y and Z are N; R² is cyclohexyl; R³, R⁴, R⁸, and R⁹ are H; mp = 137-139304 R is 4(CH₃O)—C₆H₄; X is SO; R¹ and R²¹ togehter form ═CH₂; R² iscyclohexyl, y is CH, Z is N, R³, R⁴, R⁸ and R⁹ are H - racemic mixture;mp = 122 305 R is 4(H₃CO)—C₆H₄; X is SO; R¹ and R²¹ together form ═O; R²is cyclohexyl; Y is CH; Z is N; R³, R⁴, R⁸ and R⁹ are H. 306 R is C₆H₅,X is O, R¹ and R²¹ together form

and Y and Z are N, R³, R⁴, R⁸ and R⁹ are H; mp = 144-146 (dimaleate)

[0288] In like manner compounds 600 to 804 from the previous table wereproduced with the following physical data: Com- pound Number MeltingPoint or Mass Spectral Data 600 FAB (NBA-G/TG-DMSO): 435 (M + 1), 391,338, 324 601 mp = 164-167 602 MS CALC'D 461.2030 FOUND 461.2040 603 MSCALC'D 425 FOUND 425 604 FAB (NBA-G/TG-DMSO): 471 (M + 1), 455, 411,364, 287 605 mp = 64-68 606 mp = 194-195 607 Mass Spec CI (ISOB): 408(M + 1), 381, 365, 231, 169 608 MS CALC'D 453 FOUND 453 609 Mass SpecSIMS (NBA-G/TG-DMSO): 452 (M + 1), 425, 409, 293, 232 610 Mass Spec FAB(NBA-G/TG-DMSO): 544 (M + 1), 543, 516, 232 611 MS CALC'D 467 FOUND 467612 mp = 142-145 613 Mass Spec CI: 452 (M + 1) 614 MS CALC'D 437 FOUND437 615 Mass Spec SIMS (NBA-G/TG-DMSO): 452 (M + 1), 425, 409, 293, 232616 MS CALC'D 389 FOUND 390 617 Mass Spec FAB (NBA-G/TG-DMSO): 560 (M +1), 559, 532, 433, 363 618 mp = 143-145 619 620 mp = 123-124 621 MassSpec FAB (NBA-G/TG-DMSO): 495 (M + 1), 411, 299, 283 622 mp = 205 623 mp= 212 624 Mass Spec FAB (NBA-G/TG-DMSO): 544 (M + 1), 543, 516 625 mp =132-134 626 Mass Spec FAB (NBA-G/TG-DMSO): 514 (M + 1 ), 513, 486, 240627 Mass Spec FAB (SIMS9CAL): 530 (M + 1), 425, 398 628 mp = 141-145 629mp = 151-154 630 Mass Spec FAB (NBA-G/TG-DMSO): 560 (M + 1), 559, 532631 Mass Spec FAB (SIMS4CAL): 515 (M + 1), 514, 487, 307, 289, 238 632mp = 121-124 MS CALC'D 410 FOUND 410 633 MS CALC'D 438.2200 FOUND438.2215 634 Mass Spec CI: 436 (M + 1), 409 635 mp = 190 (dec) 636 MSCALC'D 381 FOUND 382 637 mp = 225 638 MS CALC'D 441 FOUND 442 639 mp =253-255 640 Mass Spec FAB (NBA-G/TG-DMSO): 409 (M + 1), 381 641 MSCALC'D 454 FOUND 455 642 mp = 245 643 mp = 209 644 MS CALC'D 419.2698FOUND 419.2706 645 mp = 248-250 646 mp = 132-133 MS CALC'D 439 FOUND 439647 MS CALC'D 454 FOUND 455 648 mp = 210--211 649 mp = 250 650 mp =200-203 651 MS CALC'D 380.2048 FOUND 380.2047 652 mp = 129-131 MS CALC'D439 FOUND 439 653 mp = 188-189 654 MS CALC'D 394.2205 FOUND 394.2199 655MS CALC'D 451.2419 FOUND 451.2404 656 mp = 227-230 657 MS CALC'D 452FOUND 452 658 mp = 53-55 659 MS CALC'D 412.2110 FOUND 412.2111 660 MSCALC'D 412.1946 FOUND 412.1950 661 HRMS Calcd 455.2368 Found 455.2370662 MS CALC'D 430.1852 FOUND 430.1856 663 mp = 159-163 MS CALC'D 439FOUND 440 664 MS CALC'D 471.2318 FOUND 471.2327 665 MS CALC'D 381.2001FOUND 381.2000 666 MS CALC'D 410.2154 FOUND 410.2158 667 mp = 241-242668 MS CALC'D 470.2367 FOUND 470.2367 669 mp = 168-170 MS CALC'D 440FOUND 441 670 MS CALC'D 414.1903 FOUND 414.1899 671 mp = 130.5-131.5 672Mass Spec CI (CH4): 481 (M + 1), 465, 445, 357, 297, 249, 167 673 MSCALC'D 379.2208 FOUND 379.2210 674 MS:calcd for C28H35NSO4: 481 found481.7. 675 MS CALC'D 395.2157 FOUND 395.2161 676 MS:calcd forC29H37NSO4: 495; found 494 (M + 1). 677 mp = 150-151 678 Mass Spec CI(CH4): 497 (M + 1), 477, 325, 167 679 MS CALC'D 387 FOUND 388 680 MSCALC'D 413.1899 FOUND 413.1892 681 MS CALC'D 411.2106 FOUND 411.2100 682MS:calcd for C32H37NSO2: 499; found 500 (M + 1). 683 MS CALC'D 381.2001FOUND 381.1996 684 MS CALC'D 478.2028 FOUND 478.2014 685 MS:calcd forC29H37NSO3: 479; found 480.4 (M + 1). 686 MS CALC'D 397.1950 FOUND397.1954 687 MS CALC'D 462.2078 FOUND 462.2078 688 MS:calcd forC32H37NSO3: 515; found 516 (M + 1). 689 MS CALC'D 413.1899 FOUND483.1892 690 MS CALC'D 379.2208 FOUND 379.2203 691 MS CALC'D 437.2263FOUND 437.2264 692 MS CALC'D 395.2157 FOUND 395.2169 693 MS CALC'D442.2052 FOUND 442.2057 694 MS CALC'D 442.2052 FOUND 442.2057 695 MSCALC'D 456.2572 FOUND 456.2580 696 MS CALC'D 391 FOUND 391 697 MS CALC'D397.1950 FOUND 397.1954 698 MS CALC'D 516.2572 FOUND 516.2572 699 MSCALC'D 410.2154 FOUND 410.2154 700 mp = 215-218 701 MS CALC'D 456 FOUND457 702 MS CALC'D 437.2263 FOUND 437.2269 703 MS CALC'D 411.2106 FOUND411.2104 704 MS CALC'D 426.2103 FOUND 426.2117 705 MS CALC'D 440.2623FOUND 440.2632 706 mp = 215-218 707 m.p. = 165.0-170.0° C. (.2HCl) 708m.p. = 155.0-160.0° C. (.2HCl) 709 MS CALC'D 470.2001 FOUND 470.2007 710mp = 248-250 711 MS:calcd for C30H40N2SO5: 540; found 541 (M + 1). 712MS CALC'D 510.2790 FOUND 510.2787 713 MS CALC'D 466 FOUND 467 714 m.p. =141.0-142.0° C. (free base) 715 Mass Spec FAB: 485 (M + 1), 441, 253,209 716 MS CALC'D 428.1896 FOUND 428.1904 717 MS:calcd for C25H32N2SO3:440; found 441.2 (M + 1). 718 MS CALC'D 420 FOUND 421 719 MS CALC'D 514FOUND 515 720 m.p. = 90.0-95.0° C. (free base) 721 Mass Spec FAB: 485(M + 1), 391, 273, 232 722 MS CALC'D 496.1769 FOUND 496.1765 723 MSCALC'D 497.2474 FOUND 497.2460 724 MS CALC'D 466 FOUND 467 725 MS CALC'D498 FOUND 499 726 mp = 200-210 (dec) , Mass Spec MH+ = 433 727 mp = 210(dec) 728 mp = 22o deg (dec) 729 MS CALC'D 427.2419 FOUND 427.2427 730731 mp = 180 (dec) 732 mp = 200 (dec), Mass Spec MH+ = 433 733 mp = 180deg (dec) 734 mp = 215 deg (dec) 735 MS CALC'D 443.2368 FOUND 443.2367736 mp = 210 deg (dec) 737 mp = 200 deg (dec) 738 mp = 205 deg (dec) 739mp = 210 deg (dec) 740 741 mp = 205 deg (dec) 742 mp = 185 deg (dec) 743mp = 120-123 744 mp = 125-128 745 mp = 130-133 746 Mass Spec FAB(NBA-G/TG-DMSO): 480 (M + 1), 479, 452, 311 747 mp = 208-211 748 MSCALC'D 427 FOUND 428 749 mp = 131-134 750 161-163 751 FAB MS 648 (MH+)752 Mass Spec FAB (NBA-G/TG-DMSO): 511 (M + 1), 484 753 FAB: 495 (M +1), 479, 411, 311 754 MS CALC'D 439 FOUND 440 755 MS CALC'D 440.2259FOUND 440.2255 756 MS CALC'D 470 FOUND 470 757 mp = 131-132.5 758MS:calcd for C26H35NSO2: 425; found 426.3 (M + 1). 759 MS CALC'D 455FOUND 456 760 MS:calcd for C28H36N2SO5: 512; found 513.2 (M + 1). 761 MSCALC'D 456 FOUND 456 762 mp = 165-166 MS CALC'D 437 FOUND 438 763MS:calcd for C28H36N2SO4: 496; found 497.3 (M + 1). 764 MS:calcd forC26H33NSO2: 423; found 424.3 (M + 1). 765 MS:calcd for C28H36N2SO3: 480;found 481.6 (M + 1). 766 MS:calcd for C26H35NSO4: 457; found 458 (M +1). 767 MS:calcd for C26H35NSO3: 441; found 442 (M + 1). 768 mp =149-150 769 MS:calcd for C28H37NSO4: 483; found 484 (M + 1). 770 MSCALC'D 476.2071 FOUND 476.2066 771 MS:calcd for C28H38N2SO5: 514; found515.3 (M + 1). 772 mp = 142-143 773 mp = 143-144 774 MS:calcd forC28H37NSO5: 499; found 500 (M + 1). 775 MS CALC'D 460 FOUND 460 776MS:calcd for C29H37NSO5: 511; found 512 (M + 1). 777 MS:calcd forC28H41N3S2O5: 563; found 564.1 (M + 1). 779 m.p. = 150.0-152.0° C.(.2HCl) 780 m.p. = 187.0-189.0° C. (.2HCl) 781 MS:calcd for C25H31NSO4:441; found 442 (M + 1). 782 MS:calcd for C25H31NSO2: 409; found 410 (M +1). 783 MS:calcd for C28H39N3SO5: 529; found 530.7 (M + 1). 784 m.p. =155.0-157.0° C. (.2HCl) 785 m.p. = 135.0-137.0° C. (.2HCl) 786 MS calc'd511.2994 found: 511.3000 787 MS:calcd for C25H31NSO3: 425; found 426(M + 1). 788 MS:calcd for C28H39N3SO5: 529; found 530.3 (M + 1). 789MS:calcd for C28H39N3SO3: 497; found 498.4 (M + 1). 790 MS:calcd forC28H39N3SO3: 497; found 498.3 (M + 1). 791 MS:calcd for C29H41N3SO4:527; found 528.1 (M + 1). 792 mp = 205-210 793 Mass Spec CI: 375 (M + 1)794 mp = 150-152 795 mp = 224-227 796 MS:calcd for C30H43N3SO3: 525;found 526 (M + 1). 797 MS:calcd for C28H40N4SO4: 528; found 529.1 (M +1). 798 Mass Spec CI: 441 (M + 1) 799 mp = 138-140 800 mp = 143-146 801mp = 259 802 mp = 120-122 803 mp = 215-225 (dec) Mass Spec MH+ = 473 804mp = 195-205 (dec) Mass Spec MH+ = 473 805 mp = 228-230 (dec)

What is claimed:
 1. A compound having the structural formula I,

including all isomers and pharmaceutically acceptable salts, esters, andsolvates thereof, wherein one of Y and Z is N and the other is N, CH, orC-alkyl; X is —O—, —S—, —SO—, —SO₂—, —NR⁶—, —CO—, —CH₂—, —CS—,—C(OR⁵)₂—, —C(SR⁵)₂—, —CONR²⁰—, —C(alkyl)₂-, —C(H)(alkyl)-, —NR²⁰—SO₂—,—NR²⁰CO—,

R is hydrogen, acyl, alkyl, alkenyl, cycloalkyl, cycloalkyl substitutedwith up to two alkyl groups, cycloalkenyl, bicycloalkyl, arylalkenyl,benzyl, benzyl substituted with up to three independently selected R³groups, cycloalkylalkyl, polyhaloacyl, benzyloxyalkyl,hydroxyC₂-C₂₀alkyl, alkenylcarbonyl, alkylarylsulfonyl,alkoxycarbonylaminoacyl, alkylsulfonyl, or arylsulfonyl, additionally,when X is —CH₂—, R may also be —OH; in further addition, when X is notN, R may also be hydroxymethyl, in further addition, R and X may combineto form the group Prot-(NOAA)_(r)—NH— wherein r is an integer of 1 to 4,Prot is a nitrogen protecting group and when r is 1, NOAA is a naturallyoccuring amino acid or an enantiomer thereof, or when r is 2 to 4, eachNOAA is a peptide of an independently selected naturally occuring aminoacid or an enantiomer thereof; R¹ and R²¹ are independently selectedfrom the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl,bicycloalkyl, alkynyl, cyano, aminoalkyl, alkoxycarbonyl, aminocarbonyl,hydroxyguanidino, alkoxycarbonylalkyl, phenyl alkyl,alkylcarbonlyoxyalkyl,

H, —OH, (provided R¹ and R²¹ are both not —OH and Y is not N), formyl,—CO alkyl, —COacyl, —COaryl, and hydroxyalkyl; additionally R¹ and R²¹together may form the group —CH₂, ═N—OR⁵,═N—CN.═N—N(R⁵)₂, ═CH-Alkyl,alkylene,

═C(halo)₂, in further addition, R¹ and R²¹ together with the carbon atomto which they are attached may form the group

or R¹ and R²¹ together with the carbon atom to which they are attachedmay form a saturated heterocyclic ring containing 3 to 7 carbon atomsand one group selected from S, O, and NH; R² is H, alkyl, alkenyl,cycloalkyl, cycloalkyl substituted with 1 to 3 independently selected R³groups, cycloalkenyl, hydroxyC₂-C₂₀alkyl, alkynyl, alkylamide,cycloalkylalkyl, hydroxyarylalkyl, bicycloalkyl, alkynyl,acylaminoalkyl, arylalkyl, hydroxyalkoxyalkyl, azabicyclo,alkylcarbonyl, alkoxyalkyl, aminocarbonylalkyl,alkoxycarbonylaminoalkyl, alkoxycarbonylamino(alkyl)alkyl;alkylcarbonyloxyalkyl, arylhydroxyalkyl, alkylcarbonylamino(alkyl)alkyl,dialkylamino,

wherein q is an integer of 0 to 2)

(wherein R²⁹ is H, alkyl, acyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl),

(wherein Q is O, NOH, or NO-alkyl), or when Z is —CH—, R² may also bealkoxycarbonyl, hydroxymethyl, —N(R⁸)₂; R³, R⁴, R²², R²⁴, and R²⁵ areindependently selected from the group consisting of H, halo, alkoxy,benzyloxy, benzyloxy substituted by nitro or aminoalkyl, haloalkyl,polyhaloalkyl, nitro, cyano, sulfonyl, hydroxy, amino, alkylamino,formyl, alkylthio, polyhaloalkoxy, acyloxy, trialkylsilyl,alkylsulfonyl, arylsulfonyl, acyl, alkoxycarbonyl alkylsulfinyl;—OCONH₂, —OCONH-alkyl, —OCON(alkyl)₂, —NHCOO-alkyl, —NHCO-alkyl, phenyl,hydroxyalkyl, or morpholino; each R⁵ and R⁶ is independently selectedfrom the group consisting of H and alkyl, provided that when X isC(OR⁵)₂ or C(SR⁵)₂, both R⁵ groups cannot be H, and in addition, when Xis C(OR⁵)₂ or C(SR⁵)₂, the two R⁵ groups in X may be joined to form—(CH₂)_(p)- wherein p is an integer of 2 to 4; R⁷ is independentlyselected from the group consisting of H, alkyl, arylalkyl, cycloalkyl,aryl and aryl substituted with R³ and R⁴ as defined herein; each R⁸ isindependently selected from the group consisting of H, hydroxyalkyl, oralkyl or two R⁸ groups may be joined to form an alkylene group; R⁹ is H,alkyl, or acyl: R²⁰ is H, phenyl or alkyl; and R²⁷ and R²⁸ areindependently selected from the group consisting of H, alkyl,hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl,alkytthioalkyl, carboxyalkyl, imidazolyalkyl, and indolyalkyl,additionally R²⁷ and R²⁸ may combine to form an alkylene group.
 2. Acompound of claim 1 wherein Y and Z are N
 3. A compound of claim 1wherein Y is CH and Z is N
 4. A compound of claim 1 wherein R is

and X is O, SO or SO₂.
 5. A compound of any one of claims 1 or 4 whereinR³ and R⁴ are H and either R¹ is cycloalkyl, alkyl, or CN and R²¹ is Hor R¹ and R²¹ together form ═CH₂ or ═O.
 6. A compound of claim 5 whereinR is

X is O, SO or SO₂, R³ and R⁴ are H and either R¹ is cycloalkyl, alkyl,or CN and R²¹ is H or R¹ and R²¹ togather form ═CH₂ or ═O.
 7. A compoundof claim 6 wherein Y and Z are N, R¹ is cycloalkyl, alkyl or CN, R²¹ isH and R² is cycloalkyl or


8. A compound of claim 6 wherein Y is CH, Z is N, and R² is cycloalkylor


9. A compound of claim 7 wherein at least one of R²⁷ and R²⁸ is alkyl.10. A compound of claim 9 wherein one of R²⁷ or R²⁸ is methyl and theother is hydrogen.
 11. A compound of claim 7 wherein R is


12. A compound of claim 8 wherein R is


13. A compound of claim 9 wherein R is


14. A compound of claim 10 wherein R is


15. A compound as defined in claim 1 selected from the group ofcompounds represented by the formula

wherein R, X, R¹, R⁸, and R²¹ are as defined in the following table #from table of com- pounds R X R¹ R²¹ R⁸ 169 4(CH₃O)—C₆H₄ SO CN H H iso A227(−) 2-pyrimidinyl O cyclohexyl H H 289 4(CH₃O)—C₆H₄ SO CN CH₃ H 2692-pyrimidinyl O CH₃ H CH₃ 214 4(CH₃O)—C₆H₄ SO₂ CO₂CH₃ H H 2322-pyrimidinyl O i-propyl H H 123 4(CH₃O)—C₆H₄ SO CH₃ H H 2364(CH₃O)—C₆H₄ SO

H H 296 4-(CH₃O)—C₆H₄ SO CH₃ CO₂Me H

or having the structural formula


16. A compound of claim 1 selected from the group consisting ofcompounds numbers 600 to 805 of the table of such compounds appearing inthe specification.
 17. A pharmaceutical composition which comprises acompound as defined in claim 1 in combination with a pharmaceuticallyacceptable carrier.
 18. A method for treating a cognitive orneurodegenerative disease comprising administering to a patientsuffering from said disease an effective amount of a compound ofclaim
 1. 19. A method of treating a cognitive or neurodegenerativedisease comprising administering to a patient suffering from saiddisease an effective amount of a combination of a compound of claim 1with an acetylcholinesterase inhibitor.
 20. A method of treating acognitive or neurodegenerative disease comprising administering to apatient suffering from said disease an effective amount of a combinationof an acetylcholine release enhancing compound with anacetylcholinesterase inhibitor.
 21. The method of claim 20 wherein theacetylcholine release enhancing compound is an m2 selective muscarinicantagonist.
 22. The method of claim 20 wherein the acetylcholine releaseenhancing compound is an m4 selective muscarinic antagonist.
 23. A kitfor treating a cognitive or neurodegenerative disease comprising inseparate containers in a single package pharmaceutical compounds for usein combination, in one container a compound in accordance with claim 1and in a separate container an acetylcholinesterase inhibitor, saidcompound and inhibitor each being in a pharmaceutically acceptablecarrier and their combined quantities being an effective amount.
 24. Akit for treating a cognitive or neurodegenerative disease comprising inseparate containers in a single package pharmaceutical compounds for usein combination, in one container an acetylcholine release enhancingcompound and in a separate container an acetylcholinesterase inhibitor,said compound and inhibitor each being in a pharmaceutically acceptablecarrier and their combined quantities being an effective amount.
 25. Thekit of claim 24 wherein said acetylcholine release enhancing compound isan m2 selective muscarinic antagonist.
 26. The kit of claim 24 whereinsaid acetylcholine release enhancing compound is an m4 selectivemuscarinic antagonist.